alimentos bd claritromicina

12
Introduction Food–drug interactions can lead to alterations in the pharmacokinetic and pharmacodynamic profile of various drugs that may have clinical implications. Food may interact with co-administered drugs in various phases: (a) before and during gastrointestinal absorption; (b) during distribution; (c) during metab- olism; and (d) during elimination. However, food has most effect during absorption and metabolism phases (1). ere is considerable evidence to suggest that the absorption of various drugs is influenced by the presence of food in the gastrointestinal tract (2). e effects of food are not always predictable and can have clinically significant consequences. Some effects of food on the bioavailability of a drug includes: changes in gastric emptying, drug chelation, changes in the activity of drug metabolizing enzymes, changes in splanchnic blood flow and plasma protein binding, physical or chemical interaction of the meal with the drug product or drug substance, and changes in the metabolic transformation of the drug by the gastroin- testinal wall or liver (3–5). Clarithromycin is a semi-synthetic macrolide anti- biotic containing a 14-membered lactone ring (6, 7) which has a unique principle metabolite (14-hydroxy clarithromycin) that has activity equal to or greater than that of the parent drug (8–10). Clarithromycin is active intracellularly, and its action is static or bactericidal, depending on the concentration and the organism. Similar to erythromycin and azithro- mycin, clarithromycin demonstrated activity against Mycobacterium avium complex (MAC) (11–14). e activity of clarithromycin is enhanced by the forma- tion of its active metabolite, 14-hydroxy clarithromy- cin, and by its extensive distribution into the tissues. Both parent and metabolite has been shown to inhibit the strains of Haemophilus influenzae in an additive and synergistic mode (15, 16). Clarithromycin extended-release tablets are used for the treatment of adults with mild-to-moderate infection caused by susceptible strains of the Clinical Research and Regulatory Affairs, 2009; 26(4): 73–83 RESEARCH ARTICLE Comparison of effect of fasting and of five different diets on the bioavailability of single oral dose of clarithromycin 500 mg extended release tablet Sanjay J. Gurule 1 , Tausif Monif 1 , Priya Ranjan Prasad Verma 2 , and Arshad H. Khuroo 1 1 Ranbaxy Research Laboratories, Gurgaon, Haryana, India, and 2 Department of Pharmaceutical Sciences, Birla Institute of Technology, Mesra, Ranchi, India Abstract The objective of this cross-over bioavailability study on clarithromycin was to compare the bioavailability under fasting and five different diets, in 18 healthy adult male human volunteers using validated LC-MS/MS method. A single dose of clarithromycin 500 mg extended release tablet was administered at six occasions: after overnight fasting, after two vegetarian diets (high fat and low fat), two non-vegetarian diets (high fat and low fat), and low fat vegetarian rice. Serial blood samples were collected up to 36 h after dose. A statis- tically significant food effect was observed for all diets when compared to fasting treatment. Keywords: Clarithromycin; LC-MS/MS; bioavailability Address for Correspondence: Sanjay J. Gurule, Ranbaxy Research Laboratories. Plot No. GP-5, Sector 18, HSIDC, Old Delhi–Gurgaon Road, Gurgaon 122 015, Haryana, India. E-mail: [email protected] (Received 20 April 2009; revised 11 July 2009; accepted 29 July 2009) ISSN 1060-1333 print/ISSN 1532-2521 online © 2009 Informa UK Ltd DOI: 10.3109/10601330903252198 http://www.informahealthcare.com/crr

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Page 1: Alimentos BD Claritromicina

Introduction

Foodndashdrug interactions can lead to alterations in the pharmacokinetic and pharmacodynamic profile of various drugs that may have clinical implications Food may interact with co-administered drugs in various phases (a) before and during gastrointestinal absorption (b) during distribution (c) during metab-olism and (d) during elimination However food has most effect during absorption and metabolism phases (1) There is considerable evidence to suggest that the absorption of various drugs is influenced by the presence of food in the gastrointestinal tract (2) The effects of food are not always predictable and can have clinically significant consequences Some effects of food on the bioavailability of a drug includes changes in gastric emptying drug chelation changes in the activity of drug metabolizing enzymes changes in splanchnic blood flow and plasma protein binding physical or chemical interaction of the meal with the drug product or drug substance and changes in the

metabolic transformation of the drug by the gastroin-testinal wall or liver (3ndash5)

Clarithromycin is a semi-synthetic macrolide anti-biotic containing a 14-membered lactone ring (6 7) which has a unique principle metabolite (14-hydroxy clarithromycin) that has activity equal to or greater than that of the parent drug (8ndash10) Clarithromycin is active intracellularly and its action is static or bactericidal depending on the concentration and the organism Similar to erythromycin and azithro-mycin clarithromycin demonstrated activity against Mycobacterium avium complex (MAC) (11ndash14) The activity of clarithromycin is enhanced by the forma-tion of its active metabolite 14-hydroxy clarithromy-cin and by its extensive distribution into the tissues Both parent and metabolite has been shown to inhibit the strains of Haemophilus influenzae in an additive and synergistic mode (15 16)

Clarithromycin extended-release tablets are used for the treatment of adults with mild-to- moderate infection caused by susceptible strains of the

Clinical Research and Regulatory Affairs 2009 26(4) 73ndash83

R E S E A R C H A R T I C L E

Comparison of effect of fasting and of five different diets on the bioavailability of single oral dose of clarithromycin 500 mg extended release tablet

Sanjay J Gurule1 Tausif Monif1 Priya Ranjan Prasad Verma 2 and Arshad H Khuroo1

1Ranbaxy Research Laboratories Gurgaon Haryana India and 2Department of Pharmaceutical Sciences Birla Institute of Technology Mesra Ranchi India

AbstractThe objective of this cross-over bioavailability study on clarithromycin was to compare the bioavailability under fasting and five different diets in 18 healthy adult male human volunteers using validated LC-MSMS method A single dose of clarithromycin 500 mg extended release tablet was administered at six occasions after overnight fasting after two vegetarian diets (high fat and low fat) two non-vegetarian diets (high fat and low fat) and low fat vegetarian rice Serial blood samples were collected up to 36 h after dose A statis-tically significant food effect was observed for all diets when compared to fasting treatment

Keywords Clarithromycin LC-MSMS bioavailability

Address for Correspondence Sanjay J Gurule Ranbaxy Research Laboratories Plot No GP-5 Sector 18 HSIDC Old DelhindashGurgaon Road Gurgaon 122 015 Haryana India E-mail sanjayguruleranbaxycom

(Received 20 April 2009 revised 11 July 2009 accepted 29 July 2009)

ISSN 1060-1333 printISSN 1532-2521 online copy 2009 Informa UK LtdDOI 10310910601330903252198 httpwwwinformahealthcarecomcrr

Clinical Research and Regulatory Affairs2009

73

26(4)

83

1060-13331532-2521copy 2009 Informa UK Ltd10310910601330903252198

20 April 200929 July 200911 July 2009

CRR

425393

74 Sanjay J Gurule et al

designated microorganisms in the conditions stated below

Acute maxillary sinusitis due to Haemophilus 1 influenzae Moraxella catarrhalis or Streptococcus pneumonia

Acute bacterial exacerbation of chronic bronchitis 2 due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella catarrhalis or Streptococcus pneumonia and

Community-acquired pneumonia due to 3 Haemophilus influenzae Haemophilus parain-fluenzae Moraxella catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae (17)

The pharmacokinetics and tolerability of clarithro-mycin extended release (ER) have been discussed in several studies Guay et al (18) described the results of three studies of the steady-state pharmacokinetic profiles of clarithromycin and its active metabolite 14-hydroxy clarithromycin after multiple oral doses of clarithromycin 500 mg ER tablets once daily as well as the effect of administration in the fasting and fed regimen They found that the bioavailability (AUC) of the ER tablet was 30 lower when administered under fasting compared with fed conditions

Gaete et al (19) performed the compara-tive bioequivalence study on two formulations of clarithromycin 500-mg modified release tablets on 16 healthy male volunteers The plasma clarithromy-cin concentrations were determined by microbiologic assay The two products were found to be bioequiva-lent according to US Food and Drug Administration (FDA) guidelines

Cheng et al (20) investigated the effect of grapefruit juice on inhibition of clarithromycin metabolism Twelve healthy subjects were given water or grape-fruit juice before and after a clarithromycin dose of 500 mg in a randomized cross-over study They found that administration of grapefruit juice increased the time to peak concentration of both clarithromycin and 14-hydroxy clarithromycin but did not affect other pharmacokinetic parameters In a 26 healthy volunteer study Chu et al (21) investigated that food intake before administration of clarithromycin immediate-release tablets increases the bioavailabil-ity of clarithromycin by ~ 25 They also concluded that this increase was considered to have little or no clinical significance and immediate-release clarithro-mycin could be taken with or without food

Alkhalidi et al (22) evaluated the pharmacoki-netic parameters of clarithromycin extended 500 mg tablet under fasting and fatty meal conditions in

38 Jordanian volunteers The Cmax

and AUC for test and reference formulation in fed condition were found to be increased concluding the effect of food

Clarithromycin extended-release tablets pro-vide lower and later steady-state peak plasma concentrations and equivalent 24-h AUCs for both clarithromycin and its active metabolite 14-hydroxy clarithromycin relative to an equal total daily dose of clarithromycin immediate-release tablets It also provides extended absorption of clarithromycin from the gastrointestinal tract after oral administration Although the extent of formation of 14-hydroxy clari-thromycin after oral administration of clarithromycin extended release tablets (two 500-mg tablets once daily) was not affected by food administration under fasting conditions was associated with an ~ 30 lower clarithromycin AUC relative to administration with food (18) Therefore it is recommended that clarithromycin extended-release tablets should be administered with food (17)

The objective of the present study was to assess the effect of different dietary status on the clari-thromycin extended release 500 mg tablet India is a country largely inhabited by vegetarians and most non-vegetarians cannot afford to consume this diet more than once or twice a week It will there-fore be worthwhile to study the effect of isocaloric vegetarian and non-vegetarian diets (each with low and high fat content) on the oral bioavailability of clarithromycin extended release formulation In this study

Plasma concentrations were determined by rapid 1 and sensitive LC-MSMS method which is highly selective for clarithromycin and its active metabolite 14-hydroxy clarithromycin (23)

Complete validation as per regulatory requirements 2 has been done before initiating the project All parameters met acceptance limits

Study was conducted with GCP and GLP 3 compliance

Almost all types of meals were taken into account to 4 check drugndashfood interaction

Experimental methods

Materials

Clarithromycin and erythromycin were procured from USP 14-hydroxy clarithromycin was supplied from analytical department of Ranbaxy Research Laboratory Gurgaon Methanol and acetonitrile were of HPLC grade purchased from Sigma-Aldrich

Bioavailability of single oral dose of clarithromycin 75

(USA) Ammonium acetate was obtained from Fluka (Buchs Switzerland) Water was purified using Milli-Q device (Millipore Moscheim Cedex France) Drug-free human plasma of healthy volunteers was obtained from Ranbaxy Clinical Pharmacology Unit (Majeedia New Delhi India) To ensure the safety during usage all batches of plasma were screened for Hepatitis B and C HIV (human immunodefi-ciency virus) 1 and 2 malaria and syphilis Human plasma batches free of significant interference were used to prepare calibration standards and quality control samples

Clinical study design

The protocol was reviewed and approved by Jamia Hamdard Institution Review Board (IRB) All vol-unteers were healthy adult males who gave written consent before participating in the study The pro-tocol had pre-defined inclusionexclusion criteria The average (plusmn SD) age and weight of volunteers was 272 plusmn 59 years and 549 plusmn 58 kg respectively (Table 1) Prior to dosing each volunteer had undergone physi-cal examination and laboratory tests of hematologic hepatic and renal functions Only medically healthy

volunteers with clinically normal laboratory profiles were enrolled in the study

The study was designed as an open label bal-anced randomized six-treatment six-period six- sequence single-dose cross-over bioavailability study in 18 healthy adult male human volunteers None of the enrolled volunteers had history of allergy to clarithromycin and other macrolide antibiotics Volunteers did not receive any medication during the study and 2 weeks prior to start of study All the volunteers abstained from xanthine-containing food or beverages or alcohol products for 48 h prior to dosing and during housing in each period as instructed Volunteers were admitted in the clinical pharmacology unit from 12 h before dose and were discharged 24 h after dose during each period After discharge ambulatory sample collection was done at 36 h A clinical nutritionist prepared five differ-ent study diets The order of receiving treatments for each volunteer during the six periods of the study was determined according to SAS generated randomization schedule Each volunteer received one 500 mg clarithromycin extended release tablet (Ranbaxy Laboratories Ltd) with 240 mL of drinking water according to the following treatments on six different days separated by 5 days wash-out period

Treatment A A single oral dose of clarithromycin 500 mg XL tablet under fasting conditions

Treatment B A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat vegetarian diet

Treatment C A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat non-vegetarian diet

Treatment D A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian diet

Treatment E A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat non-vegetarian diet

Treatment F A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian rice diet

High-fat vegetarian diet (B) was composed of whole bullmilk (200 mL) cheese pakora (55 g) one cheese toast cheese (30 g) butter (18 g) green chatni (15 g) and roasted peanuts (20 g)

High-fat non-vegetarian diet (C) was composed of bullchicken (60 g) whole milk (240 mL) hash brown potato 120 (g) two fried eggs two bread slices and butter (8 g)

Table 1 Demographic details of study subjectsParameter Statistics n = 18Age (years) n 18

Mean 272SD 59CV 218Minimum 19Maximum 40

Age category n () 18ndash25 8 (44)26ndash30 5 (28)31ndash35 3 (17)gt 35 2 (11)

Gender n () Male 18 (100)Female 0

Height (cm) n 18Mean 1651SD 50CV 30Minimum 157Maximum 176

Weight (kg) n 18Mean 549SD 58CV 106Minimum 46Maximum 66

SD Standard deviation CV Coefficient of variation

76 Sanjay J Gurule et al

Low-fat vegetarian diet (D) was composed of four bullbread slices paneer (35 g) dalia (250 g) and fruit juice 240 (mL)

Low-fat non-vegetarian diet (E) was composed of bullfour toast slices one boiled egg boneless chicken (low fat) (30 g) dalia (220 g) fruit juice (240 mL) and one banana

Low-fat vegetarian rice diet (F) was composed of bullcooked poha (300 g) kheer and skimmed milk pow-der (300 g) and one banana

The blood samples were collected at pre-dose and at 1 2 3 4 5 6 7 8 9 10 12 16 24 and 36 h post-dose in each period Plasma was separated from blood and plasma samples were stored below minus15degC until analysis

Tolerability

Tolerability was assessed based on changes in vital signs (temperature sitting blood pressure and radial pulse) measured during volunteer admission prior to dosing and every 4 h after administration of study drug in each period until discharge In addition a physician questioned volunteers about any adverse events occurring during the study addressed them as necessary and recorded them on the appropriate raw data forms

Product assays and in vitro dissolution testing

Assays to determine the clarithromycin content of the formulation and in vitro dissolution studies were performed at Ranbaxy Research Laboratory Dissolution was performed using the US Pharmacopeia (USP) method 2 (24) with paddles rotating at 100 rpm The temperature of dissolution media was maintained at 37 plusmn 05degC and samples were withdrawn at specified intervals up to 24 h The percentage of drug dissolved was calculated based on drug concentrations

Analysis of clarithromycin and 14-hydroxy clarithromycin in plasma

The concentration of clarithromycin and 14- hydroxy clarithromycin were determined by a validated LC-MSMS method The method was validated in terms of selectivity precisionaccuracy recov-ery dilution integrity matrix effect and stability studies (23)

Pharmacokinetic methodology

WinNonlin 501 pharsight was used for pharmacoki-netic analysis of the data The non-compartmental method was used to determine C

max T

max and AUC

The area under the curve to the last measurable con-centration (AUC

0ndasht) was calculated by the linear trap-

ezoidal rule The area under the curve extrapolated to infinity (AUC

0ndashinf) was calculated as AUC

0ndasht + CtK

el

where Ct is the last measurable concentration The elimination rate constant (K

el) was obtained as the

slope of the linear regression of the log transformed plasma concentration values vs time in the terminal phase

Terminal half life (t12

) was calculated as 0693Kel

The time gt MIC (time greater than minimum inhibi-tory concentration) and AUC gt MIC at 0125 025 and 05 microgmL were calculated Bioavailability of clarithromycin and its metabolite 14-hydroxy clari-thromycin under fasting conditions and with dif-ferent diets were evaluated Effect of fat (high-fatlow-fat) effect of vegetarian and non-vegetarian diets and effect of rice on the bioavailability of clarithromycin 500 mg extended release tablet was evaluated

Statistical analysis

Statistical analysis was performed on log trans-formed pharmacokinetic parameter C

max and AUC

The log-transformed pharmacokinetic parameters were analyzed using a mixed effects ANOVA model using Type III sum of squares with the main effects of sequence period and formulations as fixed effects and subjects nested within sequence as random effect Each analysis of variance included calculation of least-squares means the difference between the adjusted formulation means and the standard error associated with the difference and a p-value less than 005 (5 level of significance) was considered statistically significant for different source of variation p-value was determined using student t-test for C

max AUC

0ndasht and AUC

0ndashinf SAS ver-

sion 91 was used as the software Ratio of means was calculated using the LSM for log-transformed C

max AUC

0ndasht and AUC

0ndashinfin

Results

There were no significant protocol deviations during the study and no drug-related adverse event has been observed Of the 18 healthy adult male volunteers originally enrolled in the study three withdrew from

Bioavailability of single oral dose of clarithromycin 77

different periods of the study for personal reasons There was no significant difference between volun-teers in terms of demographic data The data was ana-lyzed on 15 volunteers who completed all six periods of the study

One set of calibration standards and two sets of quality control samples were used for analysis of each plasma volunteer samples All batches passed the batch acceptance criteria

Figures 1 and 2 show the mean profile of clarithro-mycin and 14-hydroxy clarithromycin for single dose

of clarithromycin 500 mg XL tablet from 15 healthy human male volunteers for all treatments

Tolerability

Extended release tablet formulation of clarithromycin was well tolerated by all volunteers No adverse effects were observed during the study and no volunteer left the study with changes from baseline in vital signs or laboratory test results

Product assays and in vitro dissolution testing

As per the FDA requirements for bioavailability and bioequivalence studies of orally administered drugs the difference between drug content of test product and reference product should be lt 5 (25) In this study a single formulation was used and clarithromy-cin content was found to be 1004

Effect of food on the bioavailability of clarithromycin

Refer to Tables 2 and 3 for mean plusmn SD (standard deviation) of the pharmacokinetic parameters viz T

max C

max AUC

0ndasht AUC

0ndashinf K

el T

12 mean residence

time apparent volume of distribution and clear-ance after administration of clarithromycin 500 mg XL tablet following fasting and five different diet treatments The T

max of clarithromycin in the fasting

state was 853 plusmn 471 h Tmax

observed was 647 plusmn 292 h for high-fat vegetarian diet 626 plusmn 179 h for high-fat non-vegetarian diet 720 plusmn 211 h for low-fat veg-etarian diet 626 plusmn 103 h for low-fat non-vegetarian diet and 633 plusmn 324 h for low-fat rice diet The T

max of

14-hydroxy clarithromycin in the fasting state was 700 plusmn 325 h The T

max was 773 plusmn 228 h for high-fat

vegetarian diet 813 plusmn 192 h for low-fat vegetarian diet 773 plusmn 198 h for low-fat non-vegetarian diet and 720 plusmn 39 h for low fat rice diet The T

max for

high-fat non-vegetarian diet remained the same as fasting state

An increase in Cmax

was observed with all diets (treatments B C D E and F) for clarithromycin and 14-hydroxy clarithromycin The maximum increase in C

max was observed with the high-fat vegetarian diet

for both clarithromycin and 14-hydroxy clarithromy-cin (199 and 153 high when compared to fasting respectively) and minimum increase was observed with the low fat rice diet

AUC0ndasht

also increased like Cmax

with all diets for clarithromycin and 14-hydroxy clarithromycin and

200018001600140012001000800600400200

00 5 10 15 20

Time (hr)25 30 35 40

Linear Plot of Mean ClarithromycinConcentration Versus Time

Cla

rithr

omyc

in M

ean

Con

cent

ratio

n in

Pla

sma

(ng

mL) A A Error

B B ErrorC C ErrorD D ErrorE E ErrorF F Error

Figure 1 Mean plasma concentration (plusmn SD) time profile of clar-ithromycin after single oral dose of 500 mg XL tablet (after fast-ing and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)

700

600

500

400

300

200

100

00 5 10 15 20

Time (hr)25 30 35 40

Linear Plot of Mean 14-Hydroxy ClarithromycinConcentration Versus Time

14-H

ydro

xy C

larit

hrom

ycin

Mea

nC

once

ntra

tion

in P

lasm

a (n

gm

L) A A ErrorB B ErrorC C ErrorD D ErrorE E ErrorF F Error

Figure 2 Mean plasma concentration (plusmn SD) time profile of 14-hydroxy clarithromycin after single oral dose of 500 mg XL tablet (after fasting and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)

78 Sanjay J Gurule et al

Tabl

e 3

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on a

nd

cea

ran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

14-h

ydro

xy c

lari

thro

myc

in

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

700

plusmn 3

25

773

plusmn 2

28

700

plusmn 2

30

813

plusmn 1

92

773

plusmn 1

98

720

plusmn 3

91

Cm

ax (

ng

mL)

421

09 plusmn

127

28

645

43 plusmn

178

65

641

22 plusmn

161

72

629

33 plusmn

119

48

625

24 plusmn

129

90

447

50 plusmn

162

76

AU

C0ndash

t (h

ng

mL)

911

705

plusmn 3

808

76

106

042

1 plusmn

26

870

710

661

42

plusmn 2

998

38

106

615

6 plusmn

27

212

210

640

11

plusmn 1

761

24

861

740

plusmn 3

038

23

AU

C0ndash

inf (

hn

gm

L)11

607

83

plusmn 5

113

51

118

320

6 plusmn

27

999

812

074

86

plusmn 3

699

03

119

605

2 plusmn

30

477

811

834

27

plusmn 2

015

23

985

924

plusmn 3

657

20

Kel

(h

minus1 )

006

plusmn 0

03

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

007

plusmn 0

02

T1

2 (h

)13

07

plusmn 6

37

900

plusmn 2

59

984

plusmn 3

08

968

plusmn 2

71

948

plusmn 1

85

105

1 plusmn

31

8

Mea

n r

esid

ence

tim

e (h

)22

66

plusmn 9

25

179

0 plusmn

34

019

01

plusmn 3

49

189

9 plusmn

33

118

77

plusmn 1

92

194

7 plusmn

42

8A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

927

76 plusmn

495

75

578

86 plusmn

224

59

607

96 plusmn

179

73

602

64 plusmn

170

89

591

56 plusmn

144

81

851

77 plusmn

374

52

Cle

aran

ce (

Lh

)55

56

plusmn 3

353

447

7 plusmn

11

9744

59

plusmn 1

211

445

4 plusmn

12

6443

60

plusmn 9

06

570

8 plusmn

19

30

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Tabl

e 2

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on

and

cle

aran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

clar

ith

rom

ycin

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

853

plusmn 4

71

647

plusmn 2

92

626

plusmn 1

79

720

plusmn 2

11

626

plusmn 1

03

633

plusmn 3

24

Cm

ax

(ng

mL)

983

73 plusmn

387

90

195

865

plusmn 8

087

21

888

23 plusmn

546

12

179

771

plusmn 6

826

11

903

31 plusmn

982

40

132

773

plusmn 4

569

5

AU

C0ndash

t (h

ng

mL)

178

793

2 plusmn

10

264

7021

322

46

plusmn 7

593

70

218

438

8 plusmn

68

812

422

037

82

plusmn 9

446

55

218

821

7 plusmn

68

163

618

359

83

plusmn 5

443

58

AU

C0ndash

inf (

hn

gm

L)20

371

17

plusmn 1

121

407

225

678

9 plusmn

77

260

623

011

87

plusmn 6

538

90

232

521

5 plusmn

95

058

323

125

29

plusmn 6

508

92

196

247

7 plusmn

52

760

2

Kel

(h

minus1 )

010

plusmn 0

04

012

plusmn 0

02

011

plusmn 0

02

012

plusmn 0

04

011

plusmn 0

02

010

plusmn 0

03

T1

2 (h

)7

87 plusmn

37

75

96 plusmn

08

86

61 plusmn

13

96

38 plusmn

15

46

45 plusmn

13

07

14 plusmn

19

4

Mea

n re

sid

ence

tim

e (h

)15

83

plusmn 5

27

131

5 plusmn

21

914

10

plusmn 1

48

142

1 plusmn

17

514

15

plusmn 1

53

146

6 plusmn

22

5A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

387

35 plusmn

324

40

210

11 plusmn

74

1722

945

plusmn 1

013

722

180

plusmn 8

876

224

16 plusmn

97

8728

661

plusmn 1

291

2

Cle

aran

ce (

Lh

)37

15

plusmn 3

058

245

6 plusmn

79

123

61

plusmn 7

29

243

1 plusmn

79

523

46

plusmn 7

30

272

4 plusmn

74

3

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Bioavailability of single oral dose of clarithromycin 79

maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)

There was no significant difference in values of AUC

0ndashinf when diets were compared with fasting for

clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin

Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C

max

AUC0ndasht

and AUC0ndashinf

are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively

A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin

Effect of fat (low vs high) on the bioavailability of clarithromycin

Cmax

AUC and Tmax

remain the same between high-fat vegetarian and non-vegetarian diets for

clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K

el also

Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin

There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T

max K

el and half-life was

observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin

Statistical evaluation (treatment effect using least square means)

Significant effect was observed for Cmax

AUC0ndasht

and AUC

0ndashinf and C

max AUC

0ndasht when fasting was compared

against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C

max p-value less

than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C

max for clarithromycin and

Cmax

AUC0ndasht

and AUC0ndashinf

for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect

Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for 14-hydroxy clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804

Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532

80 Sanjay J Gurule et al

Pharmacokineticndashpharmacodynamic (PK-PD) analysis

Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL

Discussion

Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and

clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)

Alkhalidi et al (22) reported the arithmetic mean (SD) C

max for the test and reference formulation under

fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC

0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL

in the respective formulations The arithmetic mean T

max was 80 (56) and 61 (38) h In the fed study the

Cmax

and AUC of both formulations were significantly

Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)

2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629

High-fat non-vegetarian (C)

3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494

Low-fat vegetarian (D)

2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783

Low-fat non-vegetarian (E)

3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548

Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration

Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)

2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081

High-fat non-vegetarian (C)

2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080

Low-fat vegetarian (D)

2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073

Low-fat non-vegetarian (E)

2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052

Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration

Bioavailability of single oral dose of clarithromycin 81

increased relative to the fasting study The arithme-tic mean C

max of the two formulations was 11830

(6375) and 11996 (4963) ngmL The arithmetic mean AUC

0ndasht was 129812 (78490) and 118229

(57902) ngmiddothmL The arithmetic mean Tmax

was 57 (28) and 67 (25) h

In another study Guay et al (18) reported fasting C

max and AUC as 233 plusmn 070 microgmL and

359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C

max and AUC were 085 plusmn 027 microgmL and

142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T

max

values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin

Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C

max of 98373 plusmn 38790 ngmL

and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C

max

1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C

max value reported by

Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin

In this study the AUC0ndasht

values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC

0ndasht value reported by Alkhalidi et al under fast-

ing condition is 86029 hngmL for clarithromycinIncreases in C

max and AUC values were observed

in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C

max was observed when

clarithromycin was administered with a high-fat

vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)

There was no significant difference in values of T

max when diets were compared with fasting p-

values above 005 were observed when fasting Tmax

was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T

max values observed for both

clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting

The confidence intervals of Cmax

and AUC0ndasht

for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers

PK-PD analysis

Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy

82 Sanjay J Gurule et al

clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL

Conclusion

In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C

max) and extent of absorp-

tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)

Acknowledgement

This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work

Declaration of interest The authors report no con-flict of interest

References

1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255

2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392

3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351

4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334

5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628

6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398

7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152

8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53

9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76

10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37

11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312

12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534

13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569

14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911

15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413

16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526

17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007

18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577

19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177

20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929

21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36

22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843

23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003

24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with

Bioavailability of single oral dose of clarithromycin 83

tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973

25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008

26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502

27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto

28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733

29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514

Page 2: Alimentos BD Claritromicina

74 Sanjay J Gurule et al

designated microorganisms in the conditions stated below

Acute maxillary sinusitis due to Haemophilus 1 influenzae Moraxella catarrhalis or Streptococcus pneumonia

Acute bacterial exacerbation of chronic bronchitis 2 due to Haemophilus influenzae Haemophilus parainfluenzae Moraxella catarrhalis or Streptococcus pneumonia and

Community-acquired pneumonia due to 3 Haemophilus influenzae Haemophilus parain-fluenzae Moraxella catarrhalis Streptococcus pneumoniae Chlamydia pneumoniae (TWAR) or Mycoplasma pneumoniae (17)

The pharmacokinetics and tolerability of clarithro-mycin extended release (ER) have been discussed in several studies Guay et al (18) described the results of three studies of the steady-state pharmacokinetic profiles of clarithromycin and its active metabolite 14-hydroxy clarithromycin after multiple oral doses of clarithromycin 500 mg ER tablets once daily as well as the effect of administration in the fasting and fed regimen They found that the bioavailability (AUC) of the ER tablet was 30 lower when administered under fasting compared with fed conditions

Gaete et al (19) performed the compara-tive bioequivalence study on two formulations of clarithromycin 500-mg modified release tablets on 16 healthy male volunteers The plasma clarithromy-cin concentrations were determined by microbiologic assay The two products were found to be bioequiva-lent according to US Food and Drug Administration (FDA) guidelines

Cheng et al (20) investigated the effect of grapefruit juice on inhibition of clarithromycin metabolism Twelve healthy subjects were given water or grape-fruit juice before and after a clarithromycin dose of 500 mg in a randomized cross-over study They found that administration of grapefruit juice increased the time to peak concentration of both clarithromycin and 14-hydroxy clarithromycin but did not affect other pharmacokinetic parameters In a 26 healthy volunteer study Chu et al (21) investigated that food intake before administration of clarithromycin immediate-release tablets increases the bioavailabil-ity of clarithromycin by ~ 25 They also concluded that this increase was considered to have little or no clinical significance and immediate-release clarithro-mycin could be taken with or without food

Alkhalidi et al (22) evaluated the pharmacoki-netic parameters of clarithromycin extended 500 mg tablet under fasting and fatty meal conditions in

38 Jordanian volunteers The Cmax

and AUC for test and reference formulation in fed condition were found to be increased concluding the effect of food

Clarithromycin extended-release tablets pro-vide lower and later steady-state peak plasma concentrations and equivalent 24-h AUCs for both clarithromycin and its active metabolite 14-hydroxy clarithromycin relative to an equal total daily dose of clarithromycin immediate-release tablets It also provides extended absorption of clarithromycin from the gastrointestinal tract after oral administration Although the extent of formation of 14-hydroxy clari-thromycin after oral administration of clarithromycin extended release tablets (two 500-mg tablets once daily) was not affected by food administration under fasting conditions was associated with an ~ 30 lower clarithromycin AUC relative to administration with food (18) Therefore it is recommended that clarithromycin extended-release tablets should be administered with food (17)

The objective of the present study was to assess the effect of different dietary status on the clari-thromycin extended release 500 mg tablet India is a country largely inhabited by vegetarians and most non-vegetarians cannot afford to consume this diet more than once or twice a week It will there-fore be worthwhile to study the effect of isocaloric vegetarian and non-vegetarian diets (each with low and high fat content) on the oral bioavailability of clarithromycin extended release formulation In this study

Plasma concentrations were determined by rapid 1 and sensitive LC-MSMS method which is highly selective for clarithromycin and its active metabolite 14-hydroxy clarithromycin (23)

Complete validation as per regulatory requirements 2 has been done before initiating the project All parameters met acceptance limits

Study was conducted with GCP and GLP 3 compliance

Almost all types of meals were taken into account to 4 check drugndashfood interaction

Experimental methods

Materials

Clarithromycin and erythromycin were procured from USP 14-hydroxy clarithromycin was supplied from analytical department of Ranbaxy Research Laboratory Gurgaon Methanol and acetonitrile were of HPLC grade purchased from Sigma-Aldrich

Bioavailability of single oral dose of clarithromycin 75

(USA) Ammonium acetate was obtained from Fluka (Buchs Switzerland) Water was purified using Milli-Q device (Millipore Moscheim Cedex France) Drug-free human plasma of healthy volunteers was obtained from Ranbaxy Clinical Pharmacology Unit (Majeedia New Delhi India) To ensure the safety during usage all batches of plasma were screened for Hepatitis B and C HIV (human immunodefi-ciency virus) 1 and 2 malaria and syphilis Human plasma batches free of significant interference were used to prepare calibration standards and quality control samples

Clinical study design

The protocol was reviewed and approved by Jamia Hamdard Institution Review Board (IRB) All vol-unteers were healthy adult males who gave written consent before participating in the study The pro-tocol had pre-defined inclusionexclusion criteria The average (plusmn SD) age and weight of volunteers was 272 plusmn 59 years and 549 plusmn 58 kg respectively (Table 1) Prior to dosing each volunteer had undergone physi-cal examination and laboratory tests of hematologic hepatic and renal functions Only medically healthy

volunteers with clinically normal laboratory profiles were enrolled in the study

The study was designed as an open label bal-anced randomized six-treatment six-period six- sequence single-dose cross-over bioavailability study in 18 healthy adult male human volunteers None of the enrolled volunteers had history of allergy to clarithromycin and other macrolide antibiotics Volunteers did not receive any medication during the study and 2 weeks prior to start of study All the volunteers abstained from xanthine-containing food or beverages or alcohol products for 48 h prior to dosing and during housing in each period as instructed Volunteers were admitted in the clinical pharmacology unit from 12 h before dose and were discharged 24 h after dose during each period After discharge ambulatory sample collection was done at 36 h A clinical nutritionist prepared five differ-ent study diets The order of receiving treatments for each volunteer during the six periods of the study was determined according to SAS generated randomization schedule Each volunteer received one 500 mg clarithromycin extended release tablet (Ranbaxy Laboratories Ltd) with 240 mL of drinking water according to the following treatments on six different days separated by 5 days wash-out period

Treatment A A single oral dose of clarithromycin 500 mg XL tablet under fasting conditions

Treatment B A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat vegetarian diet

Treatment C A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat non-vegetarian diet

Treatment D A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian diet

Treatment E A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat non-vegetarian diet

Treatment F A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian rice diet

High-fat vegetarian diet (B) was composed of whole bullmilk (200 mL) cheese pakora (55 g) one cheese toast cheese (30 g) butter (18 g) green chatni (15 g) and roasted peanuts (20 g)

High-fat non-vegetarian diet (C) was composed of bullchicken (60 g) whole milk (240 mL) hash brown potato 120 (g) two fried eggs two bread slices and butter (8 g)

Table 1 Demographic details of study subjectsParameter Statistics n = 18Age (years) n 18

Mean 272SD 59CV 218Minimum 19Maximum 40

Age category n () 18ndash25 8 (44)26ndash30 5 (28)31ndash35 3 (17)gt 35 2 (11)

Gender n () Male 18 (100)Female 0

Height (cm) n 18Mean 1651SD 50CV 30Minimum 157Maximum 176

Weight (kg) n 18Mean 549SD 58CV 106Minimum 46Maximum 66

SD Standard deviation CV Coefficient of variation

76 Sanjay J Gurule et al

Low-fat vegetarian diet (D) was composed of four bullbread slices paneer (35 g) dalia (250 g) and fruit juice 240 (mL)

Low-fat non-vegetarian diet (E) was composed of bullfour toast slices one boiled egg boneless chicken (low fat) (30 g) dalia (220 g) fruit juice (240 mL) and one banana

Low-fat vegetarian rice diet (F) was composed of bullcooked poha (300 g) kheer and skimmed milk pow-der (300 g) and one banana

The blood samples were collected at pre-dose and at 1 2 3 4 5 6 7 8 9 10 12 16 24 and 36 h post-dose in each period Plasma was separated from blood and plasma samples were stored below minus15degC until analysis

Tolerability

Tolerability was assessed based on changes in vital signs (temperature sitting blood pressure and radial pulse) measured during volunteer admission prior to dosing and every 4 h after administration of study drug in each period until discharge In addition a physician questioned volunteers about any adverse events occurring during the study addressed them as necessary and recorded them on the appropriate raw data forms

Product assays and in vitro dissolution testing

Assays to determine the clarithromycin content of the formulation and in vitro dissolution studies were performed at Ranbaxy Research Laboratory Dissolution was performed using the US Pharmacopeia (USP) method 2 (24) with paddles rotating at 100 rpm The temperature of dissolution media was maintained at 37 plusmn 05degC and samples were withdrawn at specified intervals up to 24 h The percentage of drug dissolved was calculated based on drug concentrations

Analysis of clarithromycin and 14-hydroxy clarithromycin in plasma

The concentration of clarithromycin and 14- hydroxy clarithromycin were determined by a validated LC-MSMS method The method was validated in terms of selectivity precisionaccuracy recov-ery dilution integrity matrix effect and stability studies (23)

Pharmacokinetic methodology

WinNonlin 501 pharsight was used for pharmacoki-netic analysis of the data The non-compartmental method was used to determine C

max T

max and AUC

The area under the curve to the last measurable con-centration (AUC

0ndasht) was calculated by the linear trap-

ezoidal rule The area under the curve extrapolated to infinity (AUC

0ndashinf) was calculated as AUC

0ndasht + CtK

el

where Ct is the last measurable concentration The elimination rate constant (K

el) was obtained as the

slope of the linear regression of the log transformed plasma concentration values vs time in the terminal phase

Terminal half life (t12

) was calculated as 0693Kel

The time gt MIC (time greater than minimum inhibi-tory concentration) and AUC gt MIC at 0125 025 and 05 microgmL were calculated Bioavailability of clarithromycin and its metabolite 14-hydroxy clari-thromycin under fasting conditions and with dif-ferent diets were evaluated Effect of fat (high-fatlow-fat) effect of vegetarian and non-vegetarian diets and effect of rice on the bioavailability of clarithromycin 500 mg extended release tablet was evaluated

Statistical analysis

Statistical analysis was performed on log trans-formed pharmacokinetic parameter C

max and AUC

The log-transformed pharmacokinetic parameters were analyzed using a mixed effects ANOVA model using Type III sum of squares with the main effects of sequence period and formulations as fixed effects and subjects nested within sequence as random effect Each analysis of variance included calculation of least-squares means the difference between the adjusted formulation means and the standard error associated with the difference and a p-value less than 005 (5 level of significance) was considered statistically significant for different source of variation p-value was determined using student t-test for C

max AUC

0ndasht and AUC

0ndashinf SAS ver-

sion 91 was used as the software Ratio of means was calculated using the LSM for log-transformed C

max AUC

0ndasht and AUC

0ndashinfin

Results

There were no significant protocol deviations during the study and no drug-related adverse event has been observed Of the 18 healthy adult male volunteers originally enrolled in the study three withdrew from

Bioavailability of single oral dose of clarithromycin 77

different periods of the study for personal reasons There was no significant difference between volun-teers in terms of demographic data The data was ana-lyzed on 15 volunteers who completed all six periods of the study

One set of calibration standards and two sets of quality control samples were used for analysis of each plasma volunteer samples All batches passed the batch acceptance criteria

Figures 1 and 2 show the mean profile of clarithro-mycin and 14-hydroxy clarithromycin for single dose

of clarithromycin 500 mg XL tablet from 15 healthy human male volunteers for all treatments

Tolerability

Extended release tablet formulation of clarithromycin was well tolerated by all volunteers No adverse effects were observed during the study and no volunteer left the study with changes from baseline in vital signs or laboratory test results

Product assays and in vitro dissolution testing

As per the FDA requirements for bioavailability and bioequivalence studies of orally administered drugs the difference between drug content of test product and reference product should be lt 5 (25) In this study a single formulation was used and clarithromy-cin content was found to be 1004

Effect of food on the bioavailability of clarithromycin

Refer to Tables 2 and 3 for mean plusmn SD (standard deviation) of the pharmacokinetic parameters viz T

max C

max AUC

0ndasht AUC

0ndashinf K

el T

12 mean residence

time apparent volume of distribution and clear-ance after administration of clarithromycin 500 mg XL tablet following fasting and five different diet treatments The T

max of clarithromycin in the fasting

state was 853 plusmn 471 h Tmax

observed was 647 plusmn 292 h for high-fat vegetarian diet 626 plusmn 179 h for high-fat non-vegetarian diet 720 plusmn 211 h for low-fat veg-etarian diet 626 plusmn 103 h for low-fat non-vegetarian diet and 633 plusmn 324 h for low-fat rice diet The T

max of

14-hydroxy clarithromycin in the fasting state was 700 plusmn 325 h The T

max was 773 plusmn 228 h for high-fat

vegetarian diet 813 plusmn 192 h for low-fat vegetarian diet 773 plusmn 198 h for low-fat non-vegetarian diet and 720 plusmn 39 h for low fat rice diet The T

max for

high-fat non-vegetarian diet remained the same as fasting state

An increase in Cmax

was observed with all diets (treatments B C D E and F) for clarithromycin and 14-hydroxy clarithromycin The maximum increase in C

max was observed with the high-fat vegetarian diet

for both clarithromycin and 14-hydroxy clarithromy-cin (199 and 153 high when compared to fasting respectively) and minimum increase was observed with the low fat rice diet

AUC0ndasht

also increased like Cmax

with all diets for clarithromycin and 14-hydroxy clarithromycin and

200018001600140012001000800600400200

00 5 10 15 20

Time (hr)25 30 35 40

Linear Plot of Mean ClarithromycinConcentration Versus Time

Cla

rithr

omyc

in M

ean

Con

cent

ratio

n in

Pla

sma

(ng

mL) A A Error

B B ErrorC C ErrorD D ErrorE E ErrorF F Error

Figure 1 Mean plasma concentration (plusmn SD) time profile of clar-ithromycin after single oral dose of 500 mg XL tablet (after fast-ing and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)

700

600

500

400

300

200

100

00 5 10 15 20

Time (hr)25 30 35 40

Linear Plot of Mean 14-Hydroxy ClarithromycinConcentration Versus Time

14-H

ydro

xy C

larit

hrom

ycin

Mea

nC

once

ntra

tion

in P

lasm

a (n

gm

L) A A ErrorB B ErrorC C ErrorD D ErrorE E ErrorF F Error

Figure 2 Mean plasma concentration (plusmn SD) time profile of 14-hydroxy clarithromycin after single oral dose of 500 mg XL tablet (after fasting and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)

78 Sanjay J Gurule et al

Tabl

e 3

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on a

nd

cea

ran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

14-h

ydro

xy c

lari

thro

myc

in

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

700

plusmn 3

25

773

plusmn 2

28

700

plusmn 2

30

813

plusmn 1

92

773

plusmn 1

98

720

plusmn 3

91

Cm

ax (

ng

mL)

421

09 plusmn

127

28

645

43 plusmn

178

65

641

22 plusmn

161

72

629

33 plusmn

119

48

625

24 plusmn

129

90

447

50 plusmn

162

76

AU

C0ndash

t (h

ng

mL)

911

705

plusmn 3

808

76

106

042

1 plusmn

26

870

710

661

42

plusmn 2

998

38

106

615

6 plusmn

27

212

210

640

11

plusmn 1

761

24

861

740

plusmn 3

038

23

AU

C0ndash

inf (

hn

gm

L)11

607

83

plusmn 5

113

51

118

320

6 plusmn

27

999

812

074

86

plusmn 3

699

03

119

605

2 plusmn

30

477

811

834

27

plusmn 2

015

23

985

924

plusmn 3

657

20

Kel

(h

minus1 )

006

plusmn 0

03

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

007

plusmn 0

02

T1

2 (h

)13

07

plusmn 6

37

900

plusmn 2

59

984

plusmn 3

08

968

plusmn 2

71

948

plusmn 1

85

105

1 plusmn

31

8

Mea

n r

esid

ence

tim

e (h

)22

66

plusmn 9

25

179

0 plusmn

34

019

01

plusmn 3

49

189

9 plusmn

33

118

77

plusmn 1

92

194

7 plusmn

42

8A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

927

76 plusmn

495

75

578

86 plusmn

224

59

607

96 plusmn

179

73

602

64 plusmn

170

89

591

56 plusmn

144

81

851

77 plusmn

374

52

Cle

aran

ce (

Lh

)55

56

plusmn 3

353

447

7 plusmn

11

9744

59

plusmn 1

211

445

4 plusmn

12

6443

60

plusmn 9

06

570

8 plusmn

19

30

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Tabl

e 2

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on

and

cle

aran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

clar

ith

rom

ycin

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

853

plusmn 4

71

647

plusmn 2

92

626

plusmn 1

79

720

plusmn 2

11

626

plusmn 1

03

633

plusmn 3

24

Cm

ax

(ng

mL)

983

73 plusmn

387

90

195

865

plusmn 8

087

21

888

23 plusmn

546

12

179

771

plusmn 6

826

11

903

31 plusmn

982

40

132

773

plusmn 4

569

5

AU

C0ndash

t (h

ng

mL)

178

793

2 plusmn

10

264

7021

322

46

plusmn 7

593

70

218

438

8 plusmn

68

812

422

037

82

plusmn 9

446

55

218

821

7 plusmn

68

163

618

359

83

plusmn 5

443

58

AU

C0ndash

inf (

hn

gm

L)20

371

17

plusmn 1

121

407

225

678

9 plusmn

77

260

623

011

87

plusmn 6

538

90

232

521

5 plusmn

95

058

323

125

29

plusmn 6

508

92

196

247

7 plusmn

52

760

2

Kel

(h

minus1 )

010

plusmn 0

04

012

plusmn 0

02

011

plusmn 0

02

012

plusmn 0

04

011

plusmn 0

02

010

plusmn 0

03

T1

2 (h

)7

87 plusmn

37

75

96 plusmn

08

86

61 plusmn

13

96

38 plusmn

15

46

45 plusmn

13

07

14 plusmn

19

4

Mea

n re

sid

ence

tim

e (h

)15

83

plusmn 5

27

131

5 plusmn

21

914

10

plusmn 1

48

142

1 plusmn

17

514

15

plusmn 1

53

146

6 plusmn

22

5A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

387

35 plusmn

324

40

210

11 plusmn

74

1722

945

plusmn 1

013

722

180

plusmn 8

876

224

16 plusmn

97

8728

661

plusmn 1

291

2

Cle

aran

ce (

Lh

)37

15

plusmn 3

058

245

6 plusmn

79

123

61

plusmn 7

29

243

1 plusmn

79

523

46

plusmn 7

30

272

4 plusmn

74

3

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Bioavailability of single oral dose of clarithromycin 79

maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)

There was no significant difference in values of AUC

0ndashinf when diets were compared with fasting for

clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin

Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C

max

AUC0ndasht

and AUC0ndashinf

are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively

A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin

Effect of fat (low vs high) on the bioavailability of clarithromycin

Cmax

AUC and Tmax

remain the same between high-fat vegetarian and non-vegetarian diets for

clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K

el also

Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin

There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T

max K

el and half-life was

observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin

Statistical evaluation (treatment effect using least square means)

Significant effect was observed for Cmax

AUC0ndasht

and AUC

0ndashinf and C

max AUC

0ndasht when fasting was compared

against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C

max p-value less

than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C

max for clarithromycin and

Cmax

AUC0ndasht

and AUC0ndashinf

for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect

Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for 14-hydroxy clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804

Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532

80 Sanjay J Gurule et al

Pharmacokineticndashpharmacodynamic (PK-PD) analysis

Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL

Discussion

Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and

clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)

Alkhalidi et al (22) reported the arithmetic mean (SD) C

max for the test and reference formulation under

fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC

0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL

in the respective formulations The arithmetic mean T

max was 80 (56) and 61 (38) h In the fed study the

Cmax

and AUC of both formulations were significantly

Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)

2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629

High-fat non-vegetarian (C)

3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494

Low-fat vegetarian (D)

2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783

Low-fat non-vegetarian (E)

3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548

Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration

Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)

2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081

High-fat non-vegetarian (C)

2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080

Low-fat vegetarian (D)

2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073

Low-fat non-vegetarian (E)

2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052

Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration

Bioavailability of single oral dose of clarithromycin 81

increased relative to the fasting study The arithme-tic mean C

max of the two formulations was 11830

(6375) and 11996 (4963) ngmL The arithmetic mean AUC

0ndasht was 129812 (78490) and 118229

(57902) ngmiddothmL The arithmetic mean Tmax

was 57 (28) and 67 (25) h

In another study Guay et al (18) reported fasting C

max and AUC as 233 plusmn 070 microgmL and

359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C

max and AUC were 085 plusmn 027 microgmL and

142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T

max

values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin

Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C

max of 98373 plusmn 38790 ngmL

and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C

max

1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C

max value reported by

Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin

In this study the AUC0ndasht

values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC

0ndasht value reported by Alkhalidi et al under fast-

ing condition is 86029 hngmL for clarithromycinIncreases in C

max and AUC values were observed

in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C

max was observed when

clarithromycin was administered with a high-fat

vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)

There was no significant difference in values of T

max when diets were compared with fasting p-

values above 005 were observed when fasting Tmax

was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T

max values observed for both

clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting

The confidence intervals of Cmax

and AUC0ndasht

for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers

PK-PD analysis

Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy

82 Sanjay J Gurule et al

clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL

Conclusion

In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C

max) and extent of absorp-

tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)

Acknowledgement

This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work

Declaration of interest The authors report no con-flict of interest

References

1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255

2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392

3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351

4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334

5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628

6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398

7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152

8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53

9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76

10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37

11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312

12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534

13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569

14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911

15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413

16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526

17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007

18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577

19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177

20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929

21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36

22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843

23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003

24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with

Bioavailability of single oral dose of clarithromycin 83

tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973

25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008

26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502

27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto

28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733

29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514

Page 3: Alimentos BD Claritromicina

Bioavailability of single oral dose of clarithromycin 75

(USA) Ammonium acetate was obtained from Fluka (Buchs Switzerland) Water was purified using Milli-Q device (Millipore Moscheim Cedex France) Drug-free human plasma of healthy volunteers was obtained from Ranbaxy Clinical Pharmacology Unit (Majeedia New Delhi India) To ensure the safety during usage all batches of plasma were screened for Hepatitis B and C HIV (human immunodefi-ciency virus) 1 and 2 malaria and syphilis Human plasma batches free of significant interference were used to prepare calibration standards and quality control samples

Clinical study design

The protocol was reviewed and approved by Jamia Hamdard Institution Review Board (IRB) All vol-unteers were healthy adult males who gave written consent before participating in the study The pro-tocol had pre-defined inclusionexclusion criteria The average (plusmn SD) age and weight of volunteers was 272 plusmn 59 years and 549 plusmn 58 kg respectively (Table 1) Prior to dosing each volunteer had undergone physi-cal examination and laboratory tests of hematologic hepatic and renal functions Only medically healthy

volunteers with clinically normal laboratory profiles were enrolled in the study

The study was designed as an open label bal-anced randomized six-treatment six-period six- sequence single-dose cross-over bioavailability study in 18 healthy adult male human volunteers None of the enrolled volunteers had history of allergy to clarithromycin and other macrolide antibiotics Volunteers did not receive any medication during the study and 2 weeks prior to start of study All the volunteers abstained from xanthine-containing food or beverages or alcohol products for 48 h prior to dosing and during housing in each period as instructed Volunteers were admitted in the clinical pharmacology unit from 12 h before dose and were discharged 24 h after dose during each period After discharge ambulatory sample collection was done at 36 h A clinical nutritionist prepared five differ-ent study diets The order of receiving treatments for each volunteer during the six periods of the study was determined according to SAS generated randomization schedule Each volunteer received one 500 mg clarithromycin extended release tablet (Ranbaxy Laboratories Ltd) with 240 mL of drinking water according to the following treatments on six different days separated by 5 days wash-out period

Treatment A A single oral dose of clarithromycin 500 mg XL tablet under fasting conditions

Treatment B A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat vegetarian diet

Treatment C A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a high-fat non-vegetarian diet

Treatment D A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian diet

Treatment E A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat non-vegetarian diet

Treatment F A single oral dose of clarithromycin 500 mg XL tablet within 30 min of intake of a low-fat vegetarian rice diet

High-fat vegetarian diet (B) was composed of whole bullmilk (200 mL) cheese pakora (55 g) one cheese toast cheese (30 g) butter (18 g) green chatni (15 g) and roasted peanuts (20 g)

High-fat non-vegetarian diet (C) was composed of bullchicken (60 g) whole milk (240 mL) hash brown potato 120 (g) two fried eggs two bread slices and butter (8 g)

Table 1 Demographic details of study subjectsParameter Statistics n = 18Age (years) n 18

Mean 272SD 59CV 218Minimum 19Maximum 40

Age category n () 18ndash25 8 (44)26ndash30 5 (28)31ndash35 3 (17)gt 35 2 (11)

Gender n () Male 18 (100)Female 0

Height (cm) n 18Mean 1651SD 50CV 30Minimum 157Maximum 176

Weight (kg) n 18Mean 549SD 58CV 106Minimum 46Maximum 66

SD Standard deviation CV Coefficient of variation

76 Sanjay J Gurule et al

Low-fat vegetarian diet (D) was composed of four bullbread slices paneer (35 g) dalia (250 g) and fruit juice 240 (mL)

Low-fat non-vegetarian diet (E) was composed of bullfour toast slices one boiled egg boneless chicken (low fat) (30 g) dalia (220 g) fruit juice (240 mL) and one banana

Low-fat vegetarian rice diet (F) was composed of bullcooked poha (300 g) kheer and skimmed milk pow-der (300 g) and one banana

The blood samples were collected at pre-dose and at 1 2 3 4 5 6 7 8 9 10 12 16 24 and 36 h post-dose in each period Plasma was separated from blood and plasma samples were stored below minus15degC until analysis

Tolerability

Tolerability was assessed based on changes in vital signs (temperature sitting blood pressure and radial pulse) measured during volunteer admission prior to dosing and every 4 h after administration of study drug in each period until discharge In addition a physician questioned volunteers about any adverse events occurring during the study addressed them as necessary and recorded them on the appropriate raw data forms

Product assays and in vitro dissolution testing

Assays to determine the clarithromycin content of the formulation and in vitro dissolution studies were performed at Ranbaxy Research Laboratory Dissolution was performed using the US Pharmacopeia (USP) method 2 (24) with paddles rotating at 100 rpm The temperature of dissolution media was maintained at 37 plusmn 05degC and samples were withdrawn at specified intervals up to 24 h The percentage of drug dissolved was calculated based on drug concentrations

Analysis of clarithromycin and 14-hydroxy clarithromycin in plasma

The concentration of clarithromycin and 14- hydroxy clarithromycin were determined by a validated LC-MSMS method The method was validated in terms of selectivity precisionaccuracy recov-ery dilution integrity matrix effect and stability studies (23)

Pharmacokinetic methodology

WinNonlin 501 pharsight was used for pharmacoki-netic analysis of the data The non-compartmental method was used to determine C

max T

max and AUC

The area under the curve to the last measurable con-centration (AUC

0ndasht) was calculated by the linear trap-

ezoidal rule The area under the curve extrapolated to infinity (AUC

0ndashinf) was calculated as AUC

0ndasht + CtK

el

where Ct is the last measurable concentration The elimination rate constant (K

el) was obtained as the

slope of the linear regression of the log transformed plasma concentration values vs time in the terminal phase

Terminal half life (t12

) was calculated as 0693Kel

The time gt MIC (time greater than minimum inhibi-tory concentration) and AUC gt MIC at 0125 025 and 05 microgmL were calculated Bioavailability of clarithromycin and its metabolite 14-hydroxy clari-thromycin under fasting conditions and with dif-ferent diets were evaluated Effect of fat (high-fatlow-fat) effect of vegetarian and non-vegetarian diets and effect of rice on the bioavailability of clarithromycin 500 mg extended release tablet was evaluated

Statistical analysis

Statistical analysis was performed on log trans-formed pharmacokinetic parameter C

max and AUC

The log-transformed pharmacokinetic parameters were analyzed using a mixed effects ANOVA model using Type III sum of squares with the main effects of sequence period and formulations as fixed effects and subjects nested within sequence as random effect Each analysis of variance included calculation of least-squares means the difference between the adjusted formulation means and the standard error associated with the difference and a p-value less than 005 (5 level of significance) was considered statistically significant for different source of variation p-value was determined using student t-test for C

max AUC

0ndasht and AUC

0ndashinf SAS ver-

sion 91 was used as the software Ratio of means was calculated using the LSM for log-transformed C

max AUC

0ndasht and AUC

0ndashinfin

Results

There were no significant protocol deviations during the study and no drug-related adverse event has been observed Of the 18 healthy adult male volunteers originally enrolled in the study three withdrew from

Bioavailability of single oral dose of clarithromycin 77

different periods of the study for personal reasons There was no significant difference between volun-teers in terms of demographic data The data was ana-lyzed on 15 volunteers who completed all six periods of the study

One set of calibration standards and two sets of quality control samples were used for analysis of each plasma volunteer samples All batches passed the batch acceptance criteria

Figures 1 and 2 show the mean profile of clarithro-mycin and 14-hydroxy clarithromycin for single dose

of clarithromycin 500 mg XL tablet from 15 healthy human male volunteers for all treatments

Tolerability

Extended release tablet formulation of clarithromycin was well tolerated by all volunteers No adverse effects were observed during the study and no volunteer left the study with changes from baseline in vital signs or laboratory test results

Product assays and in vitro dissolution testing

As per the FDA requirements for bioavailability and bioequivalence studies of orally administered drugs the difference between drug content of test product and reference product should be lt 5 (25) In this study a single formulation was used and clarithromy-cin content was found to be 1004

Effect of food on the bioavailability of clarithromycin

Refer to Tables 2 and 3 for mean plusmn SD (standard deviation) of the pharmacokinetic parameters viz T

max C

max AUC

0ndasht AUC

0ndashinf K

el T

12 mean residence

time apparent volume of distribution and clear-ance after administration of clarithromycin 500 mg XL tablet following fasting and five different diet treatments The T

max of clarithromycin in the fasting

state was 853 plusmn 471 h Tmax

observed was 647 plusmn 292 h for high-fat vegetarian diet 626 plusmn 179 h for high-fat non-vegetarian diet 720 plusmn 211 h for low-fat veg-etarian diet 626 plusmn 103 h for low-fat non-vegetarian diet and 633 plusmn 324 h for low-fat rice diet The T

max of

14-hydroxy clarithromycin in the fasting state was 700 plusmn 325 h The T

max was 773 plusmn 228 h for high-fat

vegetarian diet 813 plusmn 192 h for low-fat vegetarian diet 773 plusmn 198 h for low-fat non-vegetarian diet and 720 plusmn 39 h for low fat rice diet The T

max for

high-fat non-vegetarian diet remained the same as fasting state

An increase in Cmax

was observed with all diets (treatments B C D E and F) for clarithromycin and 14-hydroxy clarithromycin The maximum increase in C

max was observed with the high-fat vegetarian diet

for both clarithromycin and 14-hydroxy clarithromy-cin (199 and 153 high when compared to fasting respectively) and minimum increase was observed with the low fat rice diet

AUC0ndasht

also increased like Cmax

with all diets for clarithromycin and 14-hydroxy clarithromycin and

200018001600140012001000800600400200

00 5 10 15 20

Time (hr)25 30 35 40

Linear Plot of Mean ClarithromycinConcentration Versus Time

Cla

rithr

omyc

in M

ean

Con

cent

ratio

n in

Pla

sma

(ng

mL) A A Error

B B ErrorC C ErrorD D ErrorE E ErrorF F Error

Figure 1 Mean plasma concentration (plusmn SD) time profile of clar-ithromycin after single oral dose of 500 mg XL tablet (after fast-ing and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)

700

600

500

400

300

200

100

00 5 10 15 20

Time (hr)25 30 35 40

Linear Plot of Mean 14-Hydroxy ClarithromycinConcentration Versus Time

14-H

ydro

xy C

larit

hrom

ycin

Mea

nC

once

ntra

tion

in P

lasm

a (n

gm

L) A A ErrorB B ErrorC C ErrorD D ErrorE E ErrorF F Error

Figure 2 Mean plasma concentration (plusmn SD) time profile of 14-hydroxy clarithromycin after single oral dose of 500 mg XL tablet (after fasting and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)

78 Sanjay J Gurule et al

Tabl

e 3

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on a

nd

cea

ran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

14-h

ydro

xy c

lari

thro

myc

in

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

700

plusmn 3

25

773

plusmn 2

28

700

plusmn 2

30

813

plusmn 1

92

773

plusmn 1

98

720

plusmn 3

91

Cm

ax (

ng

mL)

421

09 plusmn

127

28

645

43 plusmn

178

65

641

22 plusmn

161

72

629

33 plusmn

119

48

625

24 plusmn

129

90

447

50 plusmn

162

76

AU

C0ndash

t (h

ng

mL)

911

705

plusmn 3

808

76

106

042

1 plusmn

26

870

710

661

42

plusmn 2

998

38

106

615

6 plusmn

27

212

210

640

11

plusmn 1

761

24

861

740

plusmn 3

038

23

AU

C0ndash

inf (

hn

gm

L)11

607

83

plusmn 5

113

51

118

320

6 plusmn

27

999

812

074

86

plusmn 3

699

03

119

605

2 plusmn

30

477

811

834

27

plusmn 2

015

23

985

924

plusmn 3

657

20

Kel

(h

minus1 )

006

plusmn 0

03

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

007

plusmn 0

02

T1

2 (h

)13

07

plusmn 6

37

900

plusmn 2

59

984

plusmn 3

08

968

plusmn 2

71

948

plusmn 1

85

105

1 plusmn

31

8

Mea

n r

esid

ence

tim

e (h

)22

66

plusmn 9

25

179

0 plusmn

34

019

01

plusmn 3

49

189

9 plusmn

33

118

77

plusmn 1

92

194

7 plusmn

42

8A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

927

76 plusmn

495

75

578

86 plusmn

224

59

607

96 plusmn

179

73

602

64 plusmn

170

89

591

56 plusmn

144

81

851

77 plusmn

374

52

Cle

aran

ce (

Lh

)55

56

plusmn 3

353

447

7 plusmn

11

9744

59

plusmn 1

211

445

4 plusmn

12

6443

60

plusmn 9

06

570

8 plusmn

19

30

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Tabl

e 2

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on

and

cle

aran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

clar

ith

rom

ycin

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

853

plusmn 4

71

647

plusmn 2

92

626

plusmn 1

79

720

plusmn 2

11

626

plusmn 1

03

633

plusmn 3

24

Cm

ax

(ng

mL)

983

73 plusmn

387

90

195

865

plusmn 8

087

21

888

23 plusmn

546

12

179

771

plusmn 6

826

11

903

31 plusmn

982

40

132

773

plusmn 4

569

5

AU

C0ndash

t (h

ng

mL)

178

793

2 plusmn

10

264

7021

322

46

plusmn 7

593

70

218

438

8 plusmn

68

812

422

037

82

plusmn 9

446

55

218

821

7 plusmn

68

163

618

359

83

plusmn 5

443

58

AU

C0ndash

inf (

hn

gm

L)20

371

17

plusmn 1

121

407

225

678

9 plusmn

77

260

623

011

87

plusmn 6

538

90

232

521

5 plusmn

95

058

323

125

29

plusmn 6

508

92

196

247

7 plusmn

52

760

2

Kel

(h

minus1 )

010

plusmn 0

04

012

plusmn 0

02

011

plusmn 0

02

012

plusmn 0

04

011

plusmn 0

02

010

plusmn 0

03

T1

2 (h

)7

87 plusmn

37

75

96 plusmn

08

86

61 plusmn

13

96

38 plusmn

15

46

45 plusmn

13

07

14 plusmn

19

4

Mea

n re

sid

ence

tim

e (h

)15

83

plusmn 5

27

131

5 plusmn

21

914

10

plusmn 1

48

142

1 plusmn

17

514

15

plusmn 1

53

146

6 plusmn

22

5A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

387

35 plusmn

324

40

210

11 plusmn

74

1722

945

plusmn 1

013

722

180

plusmn 8

876

224

16 plusmn

97

8728

661

plusmn 1

291

2

Cle

aran

ce (

Lh

)37

15

plusmn 3

058

245

6 plusmn

79

123

61

plusmn 7

29

243

1 plusmn

79

523

46

plusmn 7

30

272

4 plusmn

74

3

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Bioavailability of single oral dose of clarithromycin 79

maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)

There was no significant difference in values of AUC

0ndashinf when diets were compared with fasting for

clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin

Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C

max

AUC0ndasht

and AUC0ndashinf

are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively

A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin

Effect of fat (low vs high) on the bioavailability of clarithromycin

Cmax

AUC and Tmax

remain the same between high-fat vegetarian and non-vegetarian diets for

clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K

el also

Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin

There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T

max K

el and half-life was

observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin

Statistical evaluation (treatment effect using least square means)

Significant effect was observed for Cmax

AUC0ndasht

and AUC

0ndashinf and C

max AUC

0ndasht when fasting was compared

against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C

max p-value less

than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C

max for clarithromycin and

Cmax

AUC0ndasht

and AUC0ndashinf

for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect

Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for 14-hydroxy clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804

Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532

80 Sanjay J Gurule et al

Pharmacokineticndashpharmacodynamic (PK-PD) analysis

Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL

Discussion

Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and

clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)

Alkhalidi et al (22) reported the arithmetic mean (SD) C

max for the test and reference formulation under

fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC

0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL

in the respective formulations The arithmetic mean T

max was 80 (56) and 61 (38) h In the fed study the

Cmax

and AUC of both formulations were significantly

Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)

2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629

High-fat non-vegetarian (C)

3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494

Low-fat vegetarian (D)

2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783

Low-fat non-vegetarian (E)

3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548

Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration

Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)

2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081

High-fat non-vegetarian (C)

2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080

Low-fat vegetarian (D)

2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073

Low-fat non-vegetarian (E)

2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052

Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration

Bioavailability of single oral dose of clarithromycin 81

increased relative to the fasting study The arithme-tic mean C

max of the two formulations was 11830

(6375) and 11996 (4963) ngmL The arithmetic mean AUC

0ndasht was 129812 (78490) and 118229

(57902) ngmiddothmL The arithmetic mean Tmax

was 57 (28) and 67 (25) h

In another study Guay et al (18) reported fasting C

max and AUC as 233 plusmn 070 microgmL and

359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C

max and AUC were 085 plusmn 027 microgmL and

142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T

max

values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin

Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C

max of 98373 plusmn 38790 ngmL

and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C

max

1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C

max value reported by

Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin

In this study the AUC0ndasht

values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC

0ndasht value reported by Alkhalidi et al under fast-

ing condition is 86029 hngmL for clarithromycinIncreases in C

max and AUC values were observed

in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C

max was observed when

clarithromycin was administered with a high-fat

vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)

There was no significant difference in values of T

max when diets were compared with fasting p-

values above 005 were observed when fasting Tmax

was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T

max values observed for both

clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting

The confidence intervals of Cmax

and AUC0ndasht

for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers

PK-PD analysis

Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy

82 Sanjay J Gurule et al

clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL

Conclusion

In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C

max) and extent of absorp-

tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)

Acknowledgement

This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work

Declaration of interest The authors report no con-flict of interest

References

1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255

2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392

3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351

4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334

5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628

6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398

7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152

8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53

9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76

10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37

11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312

12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534

13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569

14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911

15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413

16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526

17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007

18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577

19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177

20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929

21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36

22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843

23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003

24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with

Bioavailability of single oral dose of clarithromycin 83

tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973

25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008

26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502

27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto

28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733

29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514

Page 4: Alimentos BD Claritromicina

76 Sanjay J Gurule et al

Low-fat vegetarian diet (D) was composed of four bullbread slices paneer (35 g) dalia (250 g) and fruit juice 240 (mL)

Low-fat non-vegetarian diet (E) was composed of bullfour toast slices one boiled egg boneless chicken (low fat) (30 g) dalia (220 g) fruit juice (240 mL) and one banana

Low-fat vegetarian rice diet (F) was composed of bullcooked poha (300 g) kheer and skimmed milk pow-der (300 g) and one banana

The blood samples were collected at pre-dose and at 1 2 3 4 5 6 7 8 9 10 12 16 24 and 36 h post-dose in each period Plasma was separated from blood and plasma samples were stored below minus15degC until analysis

Tolerability

Tolerability was assessed based on changes in vital signs (temperature sitting blood pressure and radial pulse) measured during volunteer admission prior to dosing and every 4 h after administration of study drug in each period until discharge In addition a physician questioned volunteers about any adverse events occurring during the study addressed them as necessary and recorded them on the appropriate raw data forms

Product assays and in vitro dissolution testing

Assays to determine the clarithromycin content of the formulation and in vitro dissolution studies were performed at Ranbaxy Research Laboratory Dissolution was performed using the US Pharmacopeia (USP) method 2 (24) with paddles rotating at 100 rpm The temperature of dissolution media was maintained at 37 plusmn 05degC and samples were withdrawn at specified intervals up to 24 h The percentage of drug dissolved was calculated based on drug concentrations

Analysis of clarithromycin and 14-hydroxy clarithromycin in plasma

The concentration of clarithromycin and 14- hydroxy clarithromycin were determined by a validated LC-MSMS method The method was validated in terms of selectivity precisionaccuracy recov-ery dilution integrity matrix effect and stability studies (23)

Pharmacokinetic methodology

WinNonlin 501 pharsight was used for pharmacoki-netic analysis of the data The non-compartmental method was used to determine C

max T

max and AUC

The area under the curve to the last measurable con-centration (AUC

0ndasht) was calculated by the linear trap-

ezoidal rule The area under the curve extrapolated to infinity (AUC

0ndashinf) was calculated as AUC

0ndasht + CtK

el

where Ct is the last measurable concentration The elimination rate constant (K

el) was obtained as the

slope of the linear regression of the log transformed plasma concentration values vs time in the terminal phase

Terminal half life (t12

) was calculated as 0693Kel

The time gt MIC (time greater than minimum inhibi-tory concentration) and AUC gt MIC at 0125 025 and 05 microgmL were calculated Bioavailability of clarithromycin and its metabolite 14-hydroxy clari-thromycin under fasting conditions and with dif-ferent diets were evaluated Effect of fat (high-fatlow-fat) effect of vegetarian and non-vegetarian diets and effect of rice on the bioavailability of clarithromycin 500 mg extended release tablet was evaluated

Statistical analysis

Statistical analysis was performed on log trans-formed pharmacokinetic parameter C

max and AUC

The log-transformed pharmacokinetic parameters were analyzed using a mixed effects ANOVA model using Type III sum of squares with the main effects of sequence period and formulations as fixed effects and subjects nested within sequence as random effect Each analysis of variance included calculation of least-squares means the difference between the adjusted formulation means and the standard error associated with the difference and a p-value less than 005 (5 level of significance) was considered statistically significant for different source of variation p-value was determined using student t-test for C

max AUC

0ndasht and AUC

0ndashinf SAS ver-

sion 91 was used as the software Ratio of means was calculated using the LSM for log-transformed C

max AUC

0ndasht and AUC

0ndashinfin

Results

There were no significant protocol deviations during the study and no drug-related adverse event has been observed Of the 18 healthy adult male volunteers originally enrolled in the study three withdrew from

Bioavailability of single oral dose of clarithromycin 77

different periods of the study for personal reasons There was no significant difference between volun-teers in terms of demographic data The data was ana-lyzed on 15 volunteers who completed all six periods of the study

One set of calibration standards and two sets of quality control samples were used for analysis of each plasma volunteer samples All batches passed the batch acceptance criteria

Figures 1 and 2 show the mean profile of clarithro-mycin and 14-hydroxy clarithromycin for single dose

of clarithromycin 500 mg XL tablet from 15 healthy human male volunteers for all treatments

Tolerability

Extended release tablet formulation of clarithromycin was well tolerated by all volunteers No adverse effects were observed during the study and no volunteer left the study with changes from baseline in vital signs or laboratory test results

Product assays and in vitro dissolution testing

As per the FDA requirements for bioavailability and bioequivalence studies of orally administered drugs the difference between drug content of test product and reference product should be lt 5 (25) In this study a single formulation was used and clarithromy-cin content was found to be 1004

Effect of food on the bioavailability of clarithromycin

Refer to Tables 2 and 3 for mean plusmn SD (standard deviation) of the pharmacokinetic parameters viz T

max C

max AUC

0ndasht AUC

0ndashinf K

el T

12 mean residence

time apparent volume of distribution and clear-ance after administration of clarithromycin 500 mg XL tablet following fasting and five different diet treatments The T

max of clarithromycin in the fasting

state was 853 plusmn 471 h Tmax

observed was 647 plusmn 292 h for high-fat vegetarian diet 626 plusmn 179 h for high-fat non-vegetarian diet 720 plusmn 211 h for low-fat veg-etarian diet 626 plusmn 103 h for low-fat non-vegetarian diet and 633 plusmn 324 h for low-fat rice diet The T

max of

14-hydroxy clarithromycin in the fasting state was 700 plusmn 325 h The T

max was 773 plusmn 228 h for high-fat

vegetarian diet 813 plusmn 192 h for low-fat vegetarian diet 773 plusmn 198 h for low-fat non-vegetarian diet and 720 plusmn 39 h for low fat rice diet The T

max for

high-fat non-vegetarian diet remained the same as fasting state

An increase in Cmax

was observed with all diets (treatments B C D E and F) for clarithromycin and 14-hydroxy clarithromycin The maximum increase in C

max was observed with the high-fat vegetarian diet

for both clarithromycin and 14-hydroxy clarithromy-cin (199 and 153 high when compared to fasting respectively) and minimum increase was observed with the low fat rice diet

AUC0ndasht

also increased like Cmax

with all diets for clarithromycin and 14-hydroxy clarithromycin and

200018001600140012001000800600400200

00 5 10 15 20

Time (hr)25 30 35 40

Linear Plot of Mean ClarithromycinConcentration Versus Time

Cla

rithr

omyc

in M

ean

Con

cent

ratio

n in

Pla

sma

(ng

mL) A A Error

B B ErrorC C ErrorD D ErrorE E ErrorF F Error

Figure 1 Mean plasma concentration (plusmn SD) time profile of clar-ithromycin after single oral dose of 500 mg XL tablet (after fast-ing and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)

700

600

500

400

300

200

100

00 5 10 15 20

Time (hr)25 30 35 40

Linear Plot of Mean 14-Hydroxy ClarithromycinConcentration Versus Time

14-H

ydro

xy C

larit

hrom

ycin

Mea

nC

once

ntra

tion

in P

lasm

a (n

gm

L) A A ErrorB B ErrorC C ErrorD D ErrorE E ErrorF F Error

Figure 2 Mean plasma concentration (plusmn SD) time profile of 14-hydroxy clarithromycin after single oral dose of 500 mg XL tablet (after fasting and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)

78 Sanjay J Gurule et al

Tabl

e 3

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on a

nd

cea

ran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

14-h

ydro

xy c

lari

thro

myc

in

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

700

plusmn 3

25

773

plusmn 2

28

700

plusmn 2

30

813

plusmn 1

92

773

plusmn 1

98

720

plusmn 3

91

Cm

ax (

ng

mL)

421

09 plusmn

127

28

645

43 plusmn

178

65

641

22 plusmn

161

72

629

33 plusmn

119

48

625

24 plusmn

129

90

447

50 plusmn

162

76

AU

C0ndash

t (h

ng

mL)

911

705

plusmn 3

808

76

106

042

1 plusmn

26

870

710

661

42

plusmn 2

998

38

106

615

6 plusmn

27

212

210

640

11

plusmn 1

761

24

861

740

plusmn 3

038

23

AU

C0ndash

inf (

hn

gm

L)11

607

83

plusmn 5

113

51

118

320

6 plusmn

27

999

812

074

86

plusmn 3

699

03

119

605

2 plusmn

30

477

811

834

27

plusmn 2

015

23

985

924

plusmn 3

657

20

Kel

(h

minus1 )

006

plusmn 0

03

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

007

plusmn 0

02

T1

2 (h

)13

07

plusmn 6

37

900

plusmn 2

59

984

plusmn 3

08

968

plusmn 2

71

948

plusmn 1

85

105

1 plusmn

31

8

Mea

n r

esid

ence

tim

e (h

)22

66

plusmn 9

25

179

0 plusmn

34

019

01

plusmn 3

49

189

9 plusmn

33

118

77

plusmn 1

92

194

7 plusmn

42

8A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

927

76 plusmn

495

75

578

86 plusmn

224

59

607

96 plusmn

179

73

602

64 plusmn

170

89

591

56 plusmn

144

81

851

77 plusmn

374

52

Cle

aran

ce (

Lh

)55

56

plusmn 3

353

447

7 plusmn

11

9744

59

plusmn 1

211

445

4 plusmn

12

6443

60

plusmn 9

06

570

8 plusmn

19

30

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Tabl

e 2

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on

and

cle

aran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

clar

ith

rom

ycin

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

853

plusmn 4

71

647

plusmn 2

92

626

plusmn 1

79

720

plusmn 2

11

626

plusmn 1

03

633

plusmn 3

24

Cm

ax

(ng

mL)

983

73 plusmn

387

90

195

865

plusmn 8

087

21

888

23 plusmn

546

12

179

771

plusmn 6

826

11

903

31 plusmn

982

40

132

773

plusmn 4

569

5

AU

C0ndash

t (h

ng

mL)

178

793

2 plusmn

10

264

7021

322

46

plusmn 7

593

70

218

438

8 plusmn

68

812

422

037

82

plusmn 9

446

55

218

821

7 plusmn

68

163

618

359

83

plusmn 5

443

58

AU

C0ndash

inf (

hn

gm

L)20

371

17

plusmn 1

121

407

225

678

9 plusmn

77

260

623

011

87

plusmn 6

538

90

232

521

5 plusmn

95

058

323

125

29

plusmn 6

508

92

196

247

7 plusmn

52

760

2

Kel

(h

minus1 )

010

plusmn 0

04

012

plusmn 0

02

011

plusmn 0

02

012

plusmn 0

04

011

plusmn 0

02

010

plusmn 0

03

T1

2 (h

)7

87 plusmn

37

75

96 plusmn

08

86

61 plusmn

13

96

38 plusmn

15

46

45 plusmn

13

07

14 plusmn

19

4

Mea

n re

sid

ence

tim

e (h

)15

83

plusmn 5

27

131

5 plusmn

21

914

10

plusmn 1

48

142

1 plusmn

17

514

15

plusmn 1

53

146

6 plusmn

22

5A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

387

35 plusmn

324

40

210

11 plusmn

74

1722

945

plusmn 1

013

722

180

plusmn 8

876

224

16 plusmn

97

8728

661

plusmn 1

291

2

Cle

aran

ce (

Lh

)37

15

plusmn 3

058

245

6 plusmn

79

123

61

plusmn 7

29

243

1 plusmn

79

523

46

plusmn 7

30

272

4 plusmn

74

3

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Bioavailability of single oral dose of clarithromycin 79

maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)

There was no significant difference in values of AUC

0ndashinf when diets were compared with fasting for

clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin

Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C

max

AUC0ndasht

and AUC0ndashinf

are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively

A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin

Effect of fat (low vs high) on the bioavailability of clarithromycin

Cmax

AUC and Tmax

remain the same between high-fat vegetarian and non-vegetarian diets for

clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K

el also

Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin

There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T

max K

el and half-life was

observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin

Statistical evaluation (treatment effect using least square means)

Significant effect was observed for Cmax

AUC0ndasht

and AUC

0ndashinf and C

max AUC

0ndasht when fasting was compared

against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C

max p-value less

than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C

max for clarithromycin and

Cmax

AUC0ndasht

and AUC0ndashinf

for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect

Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for 14-hydroxy clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804

Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532

80 Sanjay J Gurule et al

Pharmacokineticndashpharmacodynamic (PK-PD) analysis

Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL

Discussion

Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and

clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)

Alkhalidi et al (22) reported the arithmetic mean (SD) C

max for the test and reference formulation under

fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC

0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL

in the respective formulations The arithmetic mean T

max was 80 (56) and 61 (38) h In the fed study the

Cmax

and AUC of both formulations were significantly

Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)

2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629

High-fat non-vegetarian (C)

3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494

Low-fat vegetarian (D)

2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783

Low-fat non-vegetarian (E)

3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548

Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration

Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)

2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081

High-fat non-vegetarian (C)

2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080

Low-fat vegetarian (D)

2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073

Low-fat non-vegetarian (E)

2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052

Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration

Bioavailability of single oral dose of clarithromycin 81

increased relative to the fasting study The arithme-tic mean C

max of the two formulations was 11830

(6375) and 11996 (4963) ngmL The arithmetic mean AUC

0ndasht was 129812 (78490) and 118229

(57902) ngmiddothmL The arithmetic mean Tmax

was 57 (28) and 67 (25) h

In another study Guay et al (18) reported fasting C

max and AUC as 233 plusmn 070 microgmL and

359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C

max and AUC were 085 plusmn 027 microgmL and

142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T

max

values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin

Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C

max of 98373 plusmn 38790 ngmL

and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C

max

1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C

max value reported by

Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin

In this study the AUC0ndasht

values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC

0ndasht value reported by Alkhalidi et al under fast-

ing condition is 86029 hngmL for clarithromycinIncreases in C

max and AUC values were observed

in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C

max was observed when

clarithromycin was administered with a high-fat

vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)

There was no significant difference in values of T

max when diets were compared with fasting p-

values above 005 were observed when fasting Tmax

was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T

max values observed for both

clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting

The confidence intervals of Cmax

and AUC0ndasht

for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers

PK-PD analysis

Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy

82 Sanjay J Gurule et al

clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL

Conclusion

In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C

max) and extent of absorp-

tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)

Acknowledgement

This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work

Declaration of interest The authors report no con-flict of interest

References

1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255

2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392

3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351

4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334

5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628

6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398

7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152

8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53

9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76

10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37

11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312

12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534

13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569

14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911

15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413

16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526

17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007

18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577

19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177

20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929

21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36

22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843

23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003

24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with

Bioavailability of single oral dose of clarithromycin 83

tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973

25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008

26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502

27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto

28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733

29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514

Page 5: Alimentos BD Claritromicina

Bioavailability of single oral dose of clarithromycin 77

different periods of the study for personal reasons There was no significant difference between volun-teers in terms of demographic data The data was ana-lyzed on 15 volunteers who completed all six periods of the study

One set of calibration standards and two sets of quality control samples were used for analysis of each plasma volunteer samples All batches passed the batch acceptance criteria

Figures 1 and 2 show the mean profile of clarithro-mycin and 14-hydroxy clarithromycin for single dose

of clarithromycin 500 mg XL tablet from 15 healthy human male volunteers for all treatments

Tolerability

Extended release tablet formulation of clarithromycin was well tolerated by all volunteers No adverse effects were observed during the study and no volunteer left the study with changes from baseline in vital signs or laboratory test results

Product assays and in vitro dissolution testing

As per the FDA requirements for bioavailability and bioequivalence studies of orally administered drugs the difference between drug content of test product and reference product should be lt 5 (25) In this study a single formulation was used and clarithromy-cin content was found to be 1004

Effect of food on the bioavailability of clarithromycin

Refer to Tables 2 and 3 for mean plusmn SD (standard deviation) of the pharmacokinetic parameters viz T

max C

max AUC

0ndasht AUC

0ndashinf K

el T

12 mean residence

time apparent volume of distribution and clear-ance after administration of clarithromycin 500 mg XL tablet following fasting and five different diet treatments The T

max of clarithromycin in the fasting

state was 853 plusmn 471 h Tmax

observed was 647 plusmn 292 h for high-fat vegetarian diet 626 plusmn 179 h for high-fat non-vegetarian diet 720 plusmn 211 h for low-fat veg-etarian diet 626 plusmn 103 h for low-fat non-vegetarian diet and 633 plusmn 324 h for low-fat rice diet The T

max of

14-hydroxy clarithromycin in the fasting state was 700 plusmn 325 h The T

max was 773 plusmn 228 h for high-fat

vegetarian diet 813 plusmn 192 h for low-fat vegetarian diet 773 plusmn 198 h for low-fat non-vegetarian diet and 720 plusmn 39 h for low fat rice diet The T

max for

high-fat non-vegetarian diet remained the same as fasting state

An increase in Cmax

was observed with all diets (treatments B C D E and F) for clarithromycin and 14-hydroxy clarithromycin The maximum increase in C

max was observed with the high-fat vegetarian diet

for both clarithromycin and 14-hydroxy clarithromy-cin (199 and 153 high when compared to fasting respectively) and minimum increase was observed with the low fat rice diet

AUC0ndasht

also increased like Cmax

with all diets for clarithromycin and 14-hydroxy clarithromycin and

200018001600140012001000800600400200

00 5 10 15 20

Time (hr)25 30 35 40

Linear Plot of Mean ClarithromycinConcentration Versus Time

Cla

rithr

omyc

in M

ean

Con

cent

ratio

n in

Pla

sma

(ng

mL) A A Error

B B ErrorC C ErrorD D ErrorE E ErrorF F Error

Figure 1 Mean plasma concentration (plusmn SD) time profile of clar-ithromycin after single oral dose of 500 mg XL tablet (after fast-ing and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)

700

600

500

400

300

200

100

00 5 10 15 20

Time (hr)25 30 35 40

Linear Plot of Mean 14-Hydroxy ClarithromycinConcentration Versus Time

14-H

ydro

xy C

larit

hrom

ycin

Mea

nC

once

ntra

tion

in P

lasm

a (n

gm

L) A A ErrorB B ErrorC C ErrorD D ErrorE E ErrorF F Error

Figure 2 Mean plasma concentration (plusmn SD) time profile of 14-hydroxy clarithromycin after single oral dose of 500 mg XL tablet (after fasting and five different diets) to healthy human subjects (n = 15) Treatment A (fasting) B (high-fat vegetarian) C (high-fat non-vegetarian) D (low-fat vegetarian) E (low-fat non-vegetarian) F (low-fat rice)

78 Sanjay J Gurule et al

Tabl

e 3

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on a

nd

cea

ran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

14-h

ydro

xy c

lari

thro

myc

in

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

700

plusmn 3

25

773

plusmn 2

28

700

plusmn 2

30

813

plusmn 1

92

773

plusmn 1

98

720

plusmn 3

91

Cm

ax (

ng

mL)

421

09 plusmn

127

28

645

43 plusmn

178

65

641

22 plusmn

161

72

629

33 plusmn

119

48

625

24 plusmn

129

90

447

50 plusmn

162

76

AU

C0ndash

t (h

ng

mL)

911

705

plusmn 3

808

76

106

042

1 plusmn

26

870

710

661

42

plusmn 2

998

38

106

615

6 plusmn

27

212

210

640

11

plusmn 1

761

24

861

740

plusmn 3

038

23

AU

C0ndash

inf (

hn

gm

L)11

607

83

plusmn 5

113

51

118

320

6 plusmn

27

999

812

074

86

plusmn 3

699

03

119

605

2 plusmn

30

477

811

834

27

plusmn 2

015

23

985

924

plusmn 3

657

20

Kel

(h

minus1 )

006

plusmn 0

03

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

007

plusmn 0

02

T1

2 (h

)13

07

plusmn 6

37

900

plusmn 2

59

984

plusmn 3

08

968

plusmn 2

71

948

plusmn 1

85

105

1 plusmn

31

8

Mea

n r

esid

ence

tim

e (h

)22

66

plusmn 9

25

179

0 plusmn

34

019

01

plusmn 3

49

189

9 plusmn

33

118

77

plusmn 1

92

194

7 plusmn

42

8A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

927

76 plusmn

495

75

578

86 plusmn

224

59

607

96 plusmn

179

73

602

64 plusmn

170

89

591

56 plusmn

144

81

851

77 plusmn

374

52

Cle

aran

ce (

Lh

)55

56

plusmn 3

353

447

7 plusmn

11

9744

59

plusmn 1

211

445

4 plusmn

12

6443

60

plusmn 9

06

570

8 plusmn

19

30

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Tabl

e 2

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on

and

cle

aran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

clar

ith

rom

ycin

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

853

plusmn 4

71

647

plusmn 2

92

626

plusmn 1

79

720

plusmn 2

11

626

plusmn 1

03

633

plusmn 3

24

Cm

ax

(ng

mL)

983

73 plusmn

387

90

195

865

plusmn 8

087

21

888

23 plusmn

546

12

179

771

plusmn 6

826

11

903

31 plusmn

982

40

132

773

plusmn 4

569

5

AU

C0ndash

t (h

ng

mL)

178

793

2 plusmn

10

264

7021

322

46

plusmn 7

593

70

218

438

8 plusmn

68

812

422

037

82

plusmn 9

446

55

218

821

7 plusmn

68

163

618

359

83

plusmn 5

443

58

AU

C0ndash

inf (

hn

gm

L)20

371

17

plusmn 1

121

407

225

678

9 plusmn

77

260

623

011

87

plusmn 6

538

90

232

521

5 plusmn

95

058

323

125

29

plusmn 6

508

92

196

247

7 plusmn

52

760

2

Kel

(h

minus1 )

010

plusmn 0

04

012

plusmn 0

02

011

plusmn 0

02

012

plusmn 0

04

011

plusmn 0

02

010

plusmn 0

03

T1

2 (h

)7

87 plusmn

37

75

96 plusmn

08

86

61 plusmn

13

96

38 plusmn

15

46

45 plusmn

13

07

14 plusmn

19

4

Mea

n re

sid

ence

tim

e (h

)15

83

plusmn 5

27

131

5 plusmn

21

914

10

plusmn 1

48

142

1 plusmn

17

514

15

plusmn 1

53

146

6 plusmn

22

5A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

387

35 plusmn

324

40

210

11 plusmn

74

1722

945

plusmn 1

013

722

180

plusmn 8

876

224

16 plusmn

97

8728

661

plusmn 1

291

2

Cle

aran

ce (

Lh

)37

15

plusmn 3

058

245

6 plusmn

79

123

61

plusmn 7

29

243

1 plusmn

79

523

46

plusmn 7

30

272

4 plusmn

74

3

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Bioavailability of single oral dose of clarithromycin 79

maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)

There was no significant difference in values of AUC

0ndashinf when diets were compared with fasting for

clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin

Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C

max

AUC0ndasht

and AUC0ndashinf

are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively

A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin

Effect of fat (low vs high) on the bioavailability of clarithromycin

Cmax

AUC and Tmax

remain the same between high-fat vegetarian and non-vegetarian diets for

clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K

el also

Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin

There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T

max K

el and half-life was

observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin

Statistical evaluation (treatment effect using least square means)

Significant effect was observed for Cmax

AUC0ndasht

and AUC

0ndashinf and C

max AUC

0ndasht when fasting was compared

against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C

max p-value less

than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C

max for clarithromycin and

Cmax

AUC0ndasht

and AUC0ndashinf

for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect

Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for 14-hydroxy clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804

Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532

80 Sanjay J Gurule et al

Pharmacokineticndashpharmacodynamic (PK-PD) analysis

Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL

Discussion

Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and

clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)

Alkhalidi et al (22) reported the arithmetic mean (SD) C

max for the test and reference formulation under

fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC

0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL

in the respective formulations The arithmetic mean T

max was 80 (56) and 61 (38) h In the fed study the

Cmax

and AUC of both formulations were significantly

Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)

2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629

High-fat non-vegetarian (C)

3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494

Low-fat vegetarian (D)

2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783

Low-fat non-vegetarian (E)

3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548

Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration

Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)

2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081

High-fat non-vegetarian (C)

2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080

Low-fat vegetarian (D)

2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073

Low-fat non-vegetarian (E)

2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052

Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration

Bioavailability of single oral dose of clarithromycin 81

increased relative to the fasting study The arithme-tic mean C

max of the two formulations was 11830

(6375) and 11996 (4963) ngmL The arithmetic mean AUC

0ndasht was 129812 (78490) and 118229

(57902) ngmiddothmL The arithmetic mean Tmax

was 57 (28) and 67 (25) h

In another study Guay et al (18) reported fasting C

max and AUC as 233 plusmn 070 microgmL and

359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C

max and AUC were 085 plusmn 027 microgmL and

142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T

max

values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin

Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C

max of 98373 plusmn 38790 ngmL

and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C

max

1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C

max value reported by

Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin

In this study the AUC0ndasht

values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC

0ndasht value reported by Alkhalidi et al under fast-

ing condition is 86029 hngmL for clarithromycinIncreases in C

max and AUC values were observed

in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C

max was observed when

clarithromycin was administered with a high-fat

vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)

There was no significant difference in values of T

max when diets were compared with fasting p-

values above 005 were observed when fasting Tmax

was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T

max values observed for both

clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting

The confidence intervals of Cmax

and AUC0ndasht

for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers

PK-PD analysis

Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy

82 Sanjay J Gurule et al

clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL

Conclusion

In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C

max) and extent of absorp-

tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)

Acknowledgement

This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work

Declaration of interest The authors report no con-flict of interest

References

1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255

2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392

3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351

4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334

5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628

6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398

7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152

8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53

9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76

10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37

11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312

12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534

13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569

14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911

15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413

16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526

17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007

18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577

19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177

20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929

21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36

22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843

23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003

24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with

Bioavailability of single oral dose of clarithromycin 83

tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973

25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008

26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502

27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto

28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733

29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514

Page 6: Alimentos BD Claritromicina

78 Sanjay J Gurule et al

Tabl

e 3

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on a

nd

cea

ran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

14-h

ydro

xy c

lari

thro

myc

in

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

700

plusmn 3

25

773

plusmn 2

28

700

plusmn 2

30

813

plusmn 1

92

773

plusmn 1

98

720

plusmn 3

91

Cm

ax (

ng

mL)

421

09 plusmn

127

28

645

43 plusmn

178

65

641

22 plusmn

161

72

629

33 plusmn

119

48

625

24 plusmn

129

90

447

50 plusmn

162

76

AU

C0ndash

t (h

ng

mL)

911

705

plusmn 3

808

76

106

042

1 plusmn

26

870

710

661

42

plusmn 2

998

38

106

615

6 plusmn

27

212

210

640

11

plusmn 1

761

24

861

740

plusmn 3

038

23

AU

C0ndash

inf (

hn

gm

L)11

607

83

plusmn 5

113

51

118

320

6 plusmn

27

999

812

074

86

plusmn 3

699

03

119

605

2 plusmn

30

477

811

834

27

plusmn 2

015

23

985

924

plusmn 3

657

20

Kel

(h

minus1 )

006

plusmn 0

03

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

008

plusmn 0

02

007

plusmn 0

02

T1

2 (h

)13

07

plusmn 6

37

900

plusmn 2

59

984

plusmn 3

08

968

plusmn 2

71

948

plusmn 1

85

105

1 plusmn

31

8

Mea

n r

esid

ence

tim

e (h

)22

66

plusmn 9

25

179

0 plusmn

34

019

01

plusmn 3

49

189

9 plusmn

33

118

77

plusmn 1

92

194

7 plusmn

42

8A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

927

76 plusmn

495

75

578

86 plusmn

224

59

607

96 plusmn

179

73

602

64 plusmn

170

89

591

56 plusmn

144

81

851

77 plusmn

374

52

Cle

aran

ce (

Lh

)55

56

plusmn 3

353

447

7 plusmn

11

9744

59

plusmn 1

211

445

4 plusmn

12

6443

60

plusmn 9

06

570

8 plusmn

19

30

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Tabl

e 2

Mea

n plusmn

SD

(st

and

ard

dev

iati

on)

of t

he

ph

arm

acok

inet

ic p

aram

eter

s vi

z T

max

C

max

A

UC

0ndasht

AU

C0ndash

inf

Kel

T

12

MR

T a

pp

aren

t vo

lum

e of

dis

trib

uti

on

and

cle

aran

ce a

fter

ad

min

istr

atio

n o

f cla

rith

rom

ycin

500

mg

XL

tab

let f

ollo

win

g fa

stin

g an

d fi

ve d

iffer

ent d

iet t

reat

men

ts (

n =

15)

for

clar

ith

rom

ycin

Fa

stin

g (A

)H

igh

-fat

ve

geta

rian

(B

)H

igh

-fat

n

on-v

eget

aria

n (

C)

Low

-fat

ve

geta

rian

(D

)L

ow-f

at

non

-veg

etar

ian

(E

)L

ow-f

at r

ice

(F)

Tm

ax (

h)

853

plusmn 4

71

647

plusmn 2

92

626

plusmn 1

79

720

plusmn 2

11

626

plusmn 1

03

633

plusmn 3

24

Cm

ax

(ng

mL)

983

73 plusmn

387

90

195

865

plusmn 8

087

21

888

23 plusmn

546

12

179

771

plusmn 6

826

11

903

31 plusmn

982

40

132

773

plusmn 4

569

5

AU

C0ndash

t (h

ng

mL)

178

793

2 plusmn

10

264

7021

322

46

plusmn 7

593

70

218

438

8 plusmn

68

812

422

037

82

plusmn 9

446

55

218

821

7 plusmn

68

163

618

359

83

plusmn 5

443

58

AU

C0ndash

inf (

hn

gm

L)20

371

17

plusmn 1

121

407

225

678

9 plusmn

77

260

623

011

87

plusmn 6

538

90

232

521

5 plusmn

95

058

323

125

29

plusmn 6

508

92

196

247

7 plusmn

52

760

2

Kel

(h

minus1 )

010

plusmn 0

04

012

plusmn 0

02

011

plusmn 0

02

012

plusmn 0

04

011

plusmn 0

02

010

plusmn 0

03

T1

2 (h

)7

87 plusmn

37

75

96 plusmn

08

86

61 plusmn

13

96

38 plusmn

15

46

45 plusmn

13

07

14 plusmn

19

4

Mea

n re

sid

ence

tim

e (h

)15

83

plusmn 5

27

131

5 plusmn

21

914

10

plusmn 1

48

142

1 plusmn

17

514

15

plusmn 1

53

146

6 plusmn

22

5A

pp

aren

t vol

um

e of

d

istr

ibu

tion

(L)

387

35 plusmn

324

40

210

11 plusmn

74

1722

945

plusmn 1

013

722

180

plusmn 8

876

224

16 plusmn

97

8728

661

plusmn 1

291

2

Cle

aran

ce (

Lh

)37

15

plusmn 3

058

245

6 plusmn

79

123

61

plusmn 7

29

243

1 plusmn

79

523

46

plusmn 7

30

272

4 plusmn

74

3

p-

valu

e le

ss th

an 0

05

ind

icat

es s

ign

ifica

nt e

ffec

t wh

en c

omp

ared

to fa

stin

g tr

eatm

ent

Bioavailability of single oral dose of clarithromycin 79

maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)

There was no significant difference in values of AUC

0ndashinf when diets were compared with fasting for

clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin

Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C

max

AUC0ndasht

and AUC0ndashinf

are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively

A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin

Effect of fat (low vs high) on the bioavailability of clarithromycin

Cmax

AUC and Tmax

remain the same between high-fat vegetarian and non-vegetarian diets for

clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K

el also

Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin

There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T

max K

el and half-life was

observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin

Statistical evaluation (treatment effect using least square means)

Significant effect was observed for Cmax

AUC0ndasht

and AUC

0ndashinf and C

max AUC

0ndasht when fasting was compared

against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C

max p-value less

than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C

max for clarithromycin and

Cmax

AUC0ndasht

and AUC0ndashinf

for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect

Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for 14-hydroxy clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804

Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532

80 Sanjay J Gurule et al

Pharmacokineticndashpharmacodynamic (PK-PD) analysis

Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL

Discussion

Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and

clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)

Alkhalidi et al (22) reported the arithmetic mean (SD) C

max for the test and reference formulation under

fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC

0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL

in the respective formulations The arithmetic mean T

max was 80 (56) and 61 (38) h In the fed study the

Cmax

and AUC of both formulations were significantly

Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)

2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629

High-fat non-vegetarian (C)

3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494

Low-fat vegetarian (D)

2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783

Low-fat non-vegetarian (E)

3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548

Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration

Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)

2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081

High-fat non-vegetarian (C)

2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080

Low-fat vegetarian (D)

2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073

Low-fat non-vegetarian (E)

2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052

Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration

Bioavailability of single oral dose of clarithromycin 81

increased relative to the fasting study The arithme-tic mean C

max of the two formulations was 11830

(6375) and 11996 (4963) ngmL The arithmetic mean AUC

0ndasht was 129812 (78490) and 118229

(57902) ngmiddothmL The arithmetic mean Tmax

was 57 (28) and 67 (25) h

In another study Guay et al (18) reported fasting C

max and AUC as 233 plusmn 070 microgmL and

359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C

max and AUC were 085 plusmn 027 microgmL and

142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T

max

values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin

Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C

max of 98373 plusmn 38790 ngmL

and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C

max

1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C

max value reported by

Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin

In this study the AUC0ndasht

values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC

0ndasht value reported by Alkhalidi et al under fast-

ing condition is 86029 hngmL for clarithromycinIncreases in C

max and AUC values were observed

in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C

max was observed when

clarithromycin was administered with a high-fat

vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)

There was no significant difference in values of T

max when diets were compared with fasting p-

values above 005 were observed when fasting Tmax

was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T

max values observed for both

clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting

The confidence intervals of Cmax

and AUC0ndasht

for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers

PK-PD analysis

Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy

82 Sanjay J Gurule et al

clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL

Conclusion

In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C

max) and extent of absorp-

tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)

Acknowledgement

This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work

Declaration of interest The authors report no con-flict of interest

References

1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255

2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392

3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351

4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334

5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628

6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398

7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152

8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53

9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76

10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37

11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312

12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534

13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569

14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911

15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413

16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526

17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007

18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577

19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177

20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929

21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36

22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843

23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003

24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with

Bioavailability of single oral dose of clarithromycin 83

tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973

25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008

26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502

27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto

28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733

29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514

Page 7: Alimentos BD Claritromicina

Bioavailability of single oral dose of clarithromycin 79

maximum increase was observed with the low-fat vegetarian diet (123 and 116 high when compared to fasting respectively)

There was no significant difference in values of AUC

0ndashinf when diets were compared with fasting for

clarithromycin and 14-hydroxy clarithromycin The maximum increase (114 high when compared with fasting) was observed with low-fat vegetarian diet for clarithromycin

Ratio of means (geometric means (LSM) based on log transformed data) and 90 confidence inter-vals for all the diet treatments vs fasting for C

max

AUC0ndasht

and AUC0ndashinf

are shown in Tables 4 and 5 for clarithromycin and 14-hydroxy clarithromycin respectively

A decrease in half-life was observed when the drug was administered under non-fasting conditions Half-life values observed under fasting condition for clarithromycin and 14-hydroxy clarithromycin was 787 plusmn 377 h and 1307 plusmn 637 h respectively and maximum decrease (596 plusmn 088 and 900 plusmn 259 respectively) was observed with high-fat vegetarian diet A significant effect was not observed for elimi-nation rate constant under fasting and non-fasting conditions for both clarithromycin and 14-hydroxy clarithromycin

Effect of fat (low vs high) on the bioavailability of clarithromycin

Cmax

AUC and Tmax

remain the same between high-fat vegetarian and non-vegetarian diets for

clarithromycin and 14-hydroxy clarithromycin There was no significant change in half-life and K

el also

Effect of vegetarian and non-vegetarian diets on the bioavailability of clarithromycin

There was no significant effect on the bioavailabil-ity when comparison is made between high-fat and low-fat vegetarian and non-vegetarian diets A slight difference in values of T

max K

el and half-life was

observed from vegetarian to non-vegetarian diets for clarithromycin and 14-hydroxy clarithromycin

Statistical evaluation (treatment effect using least square means)

Significant effect was observed for Cmax

AUC0ndasht

and AUC

0ndashinf and C

max AUC

0ndasht when fasting was compared

against other diets for clarithromycin and 14-hydroxy clarithromycin respectively For C

max p-value less

than 005 was observed (0001 and lt 00001 respec-tively) between low-fat vegetarian diet and low-fat rice diet for both clarithromycin and 14-hydroxy clarithromycin When the effect of low fat rice was compared against other diets a significant effect was observed with all diets for C

max for clarithromycin and

Cmax

AUC0ndasht

and AUC0ndashinf

for 14-hydroxy clarithromy-cin p-values greater than 005 were observed when the effect of fat (high-fat and low-fat diets) and the effect of source (vegetarian and non-vegetarian diets) was evaluated indicating an insignificant effect

Table 5 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for 14-hydroxy clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 15404 14233ndash16672 12406 11284ndash13639 11077 10051ndash12208Fasting (A) vs high-fat non-vegetarian (C) 15431 14258ndash16702 12449 11323ndash13687 11165 10131ndash12305Fasting (A) vs low-fat vegetarian (D) 15297 14133ndash16556 12452 11326ndash13690 11092 10065ndash12225Fasting (A) vs low-fat non-vegetarian (E) 15219 14061ndash16472 12633 11491ndash13889 11177 10141ndash12317Fasting (A) vs low-fat rice (F) 10480 9683ndash11343 9789 8904ndash10762 8896 8072ndash9804

Table 4 Ratio of means (least square means (LSM) based on log transferred data) and 90 confidence intervals for all the diet treatments vs fasting for C

max AUC

0ndasht and AUC

0ndashinf for clarithromycin

Treatment comparisonC

maxAUC

0ndashtAUC

0ndashinf

Ratio () CI () Ratio () CI () Ratio () CI ()Fasting (A) vs high-fat vegetarian (B) 19505 17809ndash21363 13578 12260ndash15039 12855 11564ndash14289Fasting (A) vs high-fat non-vegetarian (C) 19889 18160ndash21783 14076 12709ndash15590 13338 11999ndash14826Fasting (A) vs low-fat vegetarian (D) 18359 16763ndash20108 13753 12417ndash15232 13014 11708ndash14466Fasting (A) vs low-fat non-vegetarian (E) 19477 17783ndash21332 13943 12589ndash15443 13273 11940ndash14754Fasting (A) vs low-fat rice (F) 13762 12565ndash15072 11686 10551ndash12942 11274 10142ndash12532

80 Sanjay J Gurule et al

Pharmacokineticndashpharmacodynamic (PK-PD) analysis

Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL

Discussion

Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and

clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)

Alkhalidi et al (22) reported the arithmetic mean (SD) C

max for the test and reference formulation under

fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC

0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL

in the respective formulations The arithmetic mean T

max was 80 (56) and 61 (38) h In the fed study the

Cmax

and AUC of both formulations were significantly

Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)

2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629

High-fat non-vegetarian (C)

3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494

Low-fat vegetarian (D)

2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783

Low-fat non-vegetarian (E)

3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548

Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration

Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)

2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081

High-fat non-vegetarian (C)

2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080

Low-fat vegetarian (D)

2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073

Low-fat non-vegetarian (E)

2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052

Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration

Bioavailability of single oral dose of clarithromycin 81

increased relative to the fasting study The arithme-tic mean C

max of the two formulations was 11830

(6375) and 11996 (4963) ngmL The arithmetic mean AUC

0ndasht was 129812 (78490) and 118229

(57902) ngmiddothmL The arithmetic mean Tmax

was 57 (28) and 67 (25) h

In another study Guay et al (18) reported fasting C

max and AUC as 233 plusmn 070 microgmL and

359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C

max and AUC were 085 plusmn 027 microgmL and

142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T

max

values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin

Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C

max of 98373 plusmn 38790 ngmL

and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C

max

1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C

max value reported by

Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin

In this study the AUC0ndasht

values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC

0ndasht value reported by Alkhalidi et al under fast-

ing condition is 86029 hngmL for clarithromycinIncreases in C

max and AUC values were observed

in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C

max was observed when

clarithromycin was administered with a high-fat

vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)

There was no significant difference in values of T

max when diets were compared with fasting p-

values above 005 were observed when fasting Tmax

was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T

max values observed for both

clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting

The confidence intervals of Cmax

and AUC0ndasht

for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers

PK-PD analysis

Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy

82 Sanjay J Gurule et al

clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL

Conclusion

In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C

max) and extent of absorp-

tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)

Acknowledgement

This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work

Declaration of interest The authors report no con-flict of interest

References

1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255

2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392

3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351

4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334

5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628

6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398

7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152

8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53

9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76

10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37

11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312

12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534

13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569

14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911

15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413

16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526

17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007

18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577

19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177

20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929

21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36

22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843

23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003

24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with

Bioavailability of single oral dose of clarithromycin 83

tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973

25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008

26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502

27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto

28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733

29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514

Page 8: Alimentos BD Claritromicina

80 Sanjay J Gurule et al

Pharmacokineticndashpharmacodynamic (PK-PD) analysis

Time gt MIC and AUC gt MIC was calculated for clari-thromycin and 14-hydroxy clarithromycin at 0125 025 and 05 microgmL (Tables 6 and 7) There is no significant effect on Time gt MIC when different diets are compared with fasting however the diet treat-ments used in the study have a significant effect when AUC gt MIC was compared with fasting for clarithro-mycin The diet treatments used in the study have a significant effect when Time gt MIC and AUC gt MIC was compared with fasting for 14-hydroxy clarithro-mycin at 05 microgmL

Discussion

Interactions between food and drugs may inadvert-ently reduce or increase the drug effect The major-ity of clinically important foodndashdrug interactions are caused by food-induced changes in the bio-availability of the drug Since the bioavailability and

clinical effect of most drugs are correlated the bio-availability is an important pharmacokinetic effect parameter (26) The type and size of a meal may have a marked effect on the nature of a drugndashfood interaction Liquid meals which are often used in an attempt to obtain mechanistic information might have a totally different effect on drug absorption compared with solid meals which are nonetheless more clinically relevant The time interval between eating and medication will also affect the nature and extent of a drugndashfood interaction Knowing that both the nature of the food and formulation of the drug play an important role in bioavailability it becomes essential to precisely define their interac-tion (27)

Alkhalidi et al (22) reported the arithmetic mean (SD) C

max for the test and reference formulation under

fasting condition as 5694 (1893) ngmL and 6412 (2020) ngmL respectively The arithmetic mean AUC

0ndasht was 86029 (41051) and 82453 (41224) ngmiddothmL

in the respective formulations The arithmetic mean T

max was 80 (56) and 61 (38) h In the fed study the

Cmax

and AUC of both formulations were significantly

Table 6 Time and AUC above MIC (0125 025 and 05 microgmL) for clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2953 plusmn 765 1422 plusmn 955 2432 plusmn 1001 1087 plusmn 869 1665 plusmn 1035 574 plusmn 661High-fat vegetarian (B)

2954 plusmn 321 1778 plusmn 736 2358 plusmn 375 1449 plusmn 703 1574 plusmn 369 963 plusmn 629

High-fat non-vegetarian (C)

3063 plusmn 336 1803 plusmn 637 2479 plusmn 466 1458 plusmn 596 1688 plusmn 502 946 plusmn 494

Low-fat vegetarian (D)

2968 plusmn 412 1835 plusmn 913 2430 plusmn 471 1500 plusmn 875 1635 plusmn 481 999 plusmn 783

Low-fat non-vegetarian (E)

3019 plusmn 192 1814 plusmn 648 2416 plusmn 317 1477 plusmn 621 1624 plusmn 384 983 plusmn 548

Low-fat rice (F) 3062 plusmn 309 1450 plusmn 518 2459 plusmn 436 1105 plusmn 494 1585 plusmn 486 605 plusmn 426MIC Minimum inhibitory concentration

Table 7 Time and AUC above MIC (0125 025 and 05 microgmL) for 14-hydroxy clarithromycin

TreatmentsTime gt MIC

(0125 microgmL) in h

AUC gt MIC (0125 microgmL) in

hmicrogmLTime gt MIC

(025 microgmL) in h

AUC gt MIC (025 microgmL) in

hmicrogmLTime gt MIC

(05 microgmL) in h

AUC gt MIC (05 microgmL) in

hmicrogmLFasting (A) 2848 plusmn 890 516 plusmn 326 1696 plusmn 1123 221 plusmn 229 191 plusmn 480 009 plusmn 029High-fat vegetarian (B)

2888 plusmn 380 664 plusmn 244 1898 plusmn 480 368 plusmn 196 578 plusmn 487 080 plusmn 081

High-fat non-vegetarian (C)

2892 plusmn 345 665 plusmn 276 1927 plusmn 568 365 plusmn 220 567 plusmn 435 068 plusmn 080

Low-fat vegetarian (D)

2880 plusmn 430 669 plusmn 242 1961 plusmn 522 369 plusmn 191 633 plusmn 413 064 plusmn 073

Low-fat non-vegetarian (E)

2920 plusmn 250 658 plusmn 168 1939 plusmn 371 357 plusmn 135 491 plusmn 366 054 plusmn 052

Low-fat rice (F) 2739 plusmn 507 459 plusmn 283 1512 plusmn 863 197 plusmn 206 245 plusmn 392 024 plusmn 052MIC Minimum inhibitory concentration

Bioavailability of single oral dose of clarithromycin 81

increased relative to the fasting study The arithme-tic mean C

max of the two formulations was 11830

(6375) and 11996 (4963) ngmL The arithmetic mean AUC

0ndasht was 129812 (78490) and 118229

(57902) ngmiddothmL The arithmetic mean Tmax

was 57 (28) and 67 (25) h

In another study Guay et al (18) reported fasting C

max and AUC as 233 plusmn 070 microgmL and

359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C

max and AUC were 085 plusmn 027 microgmL and

142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T

max

values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin

Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C

max of 98373 plusmn 38790 ngmL

and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C

max

1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C

max value reported by

Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin

In this study the AUC0ndasht

values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC

0ndasht value reported by Alkhalidi et al under fast-

ing condition is 86029 hngmL for clarithromycinIncreases in C

max and AUC values were observed

in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C

max was observed when

clarithromycin was administered with a high-fat

vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)

There was no significant difference in values of T

max when diets were compared with fasting p-

values above 005 were observed when fasting Tmax

was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T

max values observed for both

clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting

The confidence intervals of Cmax

and AUC0ndasht

for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers

PK-PD analysis

Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy

82 Sanjay J Gurule et al

clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL

Conclusion

In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C

max) and extent of absorp-

tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)

Acknowledgement

This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work

Declaration of interest The authors report no con-flict of interest

References

1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255

2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392

3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351

4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334

5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628

6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398

7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152

8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53

9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76

10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37

11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312

12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534

13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569

14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911

15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413

16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526

17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007

18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577

19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177

20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929

21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36

22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843

23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003

24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with

Bioavailability of single oral dose of clarithromycin 83

tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973

25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008

26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502

27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto

28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733

29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514

Page 9: Alimentos BD Claritromicina

Bioavailability of single oral dose of clarithromycin 81

increased relative to the fasting study The arithme-tic mean C

max of the two formulations was 11830

(6375) and 11996 (4963) ngmL The arithmetic mean AUC

0ndasht was 129812 (78490) and 118229

(57902) ngmiddothmL The arithmetic mean Tmax

was 57 (28) and 67 (25) h

In another study Guay et al (18) reported fasting C

max and AUC as 233 plusmn 070 microgmL and

359 plusmn 124 microghmL and fed 391 plusmn 104 microgmL and 492 plusmn 105 microghmL respectively for clarithromycin Fasting C

max and AUC were 085 plusmn 027 microgmL and

142 plusmn 37 microghmL and fed 085 plusmn 020 microgmL and 146 plusmn 31 microghmL respectively for 14-hydroxy clar-ithromycin There is no significant difference in T

max

values under fasting and non-fasting conditions for clarithromycin whereas it increased in non-fasting conditions for 14-hydroxy clarithromycin This indi-cates that food has a significant effect on the phar-macokinetic parameters of clarithromycin

Since a vast majority of the Indian population is vegetarian it seemed prudent to further define the interaction with the administration of clarithromy-cin extended release tablet formulation along with equicaloric diets which varied both in content and source Hence this study was planned to compare the effect of five different diets viz high-fat vegetarian diet high-fat non-vegetarian diet low-fat vegetarian diet low-fat non-vegetarian low-fat rice and fasting state on the bioavailability of clarithromycin in nor-mal human subjects The fasting state served as ref-erence for comparison In this study a 500 mg oral dose of clarithromycin extended tablet under fasting conditions produced a C

max of 98373 plusmn 38790 ngmL

and 42109 plusmn 12728 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) (C

max

1160 ngmL and 425 ngmL for clarithromycin and 14-hydroxy clarithromycin respectively if extrapo-lated to a single dose) The C

max value reported by

Alkhalidi et al (22) under fasting condition is low compared to this study for clarithromycin

In this study the AUC0ndasht

values observed under fasting condition were 1787932 plusmn 1026470 hngmL and 911705 plusmn 380876 hngmL for clarithromycin and 14-hydroxy clarithromycin respectively This value is in close agreement with Guay et al (18) The AUC

0ndasht value reported by Alkhalidi et al under fast-

ing condition is 86029 hngmL for clarithromycinIncreases in C

max and AUC values were observed

in this study when clarithromycin was given under non-fasting conditions compared to fasting condi-tion The increase in the values was not the same for all diets when compared with the fasting treatment The maximum increase in C

max was observed when

clarithromycin was administered with a high-fat

vegetarian diet The maximum increase in AUC was observed with low-fat vegetarian diet The reason could be one of the meal components in these diets In general fatty meals will increase the extent of bioavailability of BCS class 2 compounds This might be the probable cause of increasing the overall bio-availability of clarithromycin being a BCS class 2 compound This increased bioavailability with a concomitant high-fat meal could be due to inhibi-tion of efflux transporters such as P-gp in the intes-tine (28)

There was no significant difference in values of T

max when diets were compared with fasting p-

values above 005 were observed when fasting Tmax

was compared with other diets for both clarithro-mycin and 14-hydroxy clarithromycin indicating an insignificant effect T

max values observed for both

clarithromycin and 14-hydroxy clarithromycin are as per the reported literature (18 22) In our study the half-life under fasting condition was 787 plusmn 377 h and 1307 plusmn 637 h for clarithromycin and 14- hydroxy clarithromycin respectively A decrease in half-life was observed when the drug was adminis-tered under non-fasting conditions The maximum decrease was observed with high-fat vegetarian diet However Alkhalidi et al (22) reported an increase in half-life in non-fasting conditions compared to fasting

The confidence intervals of Cmax

and AUC0ndasht

for log transformed data for treatment comparisons of fast-ing against all diets are not within 80ndash125 for clari-thromycin and 14-hydroxy clarithromycin except for the low-fat vegetarian rice diet for 14-hydroxy clarithromycin Thus the results indicate a significant effect of food in Indian volunteers

PK-PD analysis

Patterns of antimicrobial activity fall into one of the two major patterns time-dependent killing (time gt MIC) and concentration-dependent killing (AUC gt MIC) Macrolide antibiotics (clarithromy-cin) fall under the time-dependent category (29) The relationship between time greater than MIC and resistance selection for time-dependent anti-microbials have not been well characterized In the present study the antimicrobial activity was analyzed at three different concentrations levels ie 0125 025 and 05 microgmL There is no signifi-cant effect on Time gt MIC when different diets are compared with fasting AUC gt MIC under fasting conditions was 1422 plusmn 955 1087 plusmn 869 and 574 plusmn 661 hmicrogmL for clarithromycin and 516 plusmn 326 221 plusmn 229 and 009 plusmn 029 hmicrogmL for 14-hydroxy

82 Sanjay J Gurule et al

clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL

Conclusion

In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C

max) and extent of absorp-

tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)

Acknowledgement

This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work

Declaration of interest The authors report no con-flict of interest

References

1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255

2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392

3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351

4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334

5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628

6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398

7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152

8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53

9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76

10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37

11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312

12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534

13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569

14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911

15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413

16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526

17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007

18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577

19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177

20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929

21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36

22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843

23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003

24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with

Bioavailability of single oral dose of clarithromycin 83

tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973

25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008

26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502

27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto

28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733

29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514

Page 10: Alimentos BD Claritromicina

82 Sanjay J Gurule et al

clarithromycin respectively All diets increased the AUC gt MIC The maximum increase was observed with the low-fat vegetarian diet (1835 plusmn 913 1500 plusmn 875 and 999 plusmn 783 hmicrogmL respectively) for clarithromycin The low-fat vegetarian diet increases AUC gt MIC for 14-hydroxy clarithromycin at 0125 and 025 microgmL

Conclusion

In this study in healthy Indian subjects a significant food effect was observed as indicated by a significant increase in both the rate (C

max) and extent of absorp-

tion (AUC) when fasting was compared with high-fat and low-fat vegetarian and non-vegetarian diets Administration of clarithromycin 500 mg extended release tablet under fasting condition was associ-ated with lower rate and extent of absorption relative to administration with food There was no signifi-cant effect on the bioavailability of clarithromycin when comparison is made between fat content (low and high) and source of food (vegetarian or non-vegetarian)

Acknowledgement

This paper is part of PhD thesis of Sanjay Gurule The author thanks Ranbaxy research labs Gurgaon India for carrying out this work

Declaration of interest The authors report no con-flict of interest

References

1 Singh BN Effects of food on clinical pharmacokinetics Clin Pharmacokinet 199937213ndash255

2 Shargel L Wu-pong S Andrew BC Applied biopharmaceu-tics and pharmacokinetics5th Ed NJ USA McGraw Hill Medical 2005p 391ndash392

3 Melander A Influence of food on the bioavailability of drugs Clin Pharmacokinet 19783337ndash351

4 Welling PG Influence of food and diet on GI drug absorption a review J Pharmacokinet Pharmacodyn 19775291ndash334

5 Winstanley PA Orme MLE The effects of food on drug bio-availability Br J Clin Pharm 198928621ndash628

6 Rodvold KA Clinical pharmacokinetics of clarithromycin Clin Pharmacokin 199937385ndash398

7 Piscitelli SC Danziger LH Rodvold KA Clarithromycin and azithromycin new macrolide antibiotics Clin Pharm 199211137ndash152

8 Hardy DJ Guay DRP Jones RN Clarithromycin a unique macrolide a pharmacokinetic macrobiological and clini-cal overview Diagn Microbiol Infect Dis 19921539ndash53

9 Fernandez PB Ramer R Rode RA Freiberg LA Bioassay for A-56268 (TE-031) and identification of its major metabolite 14-hydroxy-6- O-methyl erythromycin Eur J Clin Microbiol Infect Dis 1988773ndash76

10 Davey PG The pharmacokinetics of clarithromycin and its 14-OH metabolite J Hosp Infect 19911929ndash37

11 Barradell LB Plosker GL McTavish D Clarithromycin a review of its pharmacological properties and therapeutic use in Mycobacterium aviumintracellulare complex infec-tion in patients with acquired immunodeficiency syndrome Drugs 199346289ndash312

12 Fernandes PB Hardy DJ McDaniel D Hanson CW Swanson RN In vitro and in vivo activities of clarithro-mycin against Mycobacterium avium Antimicrob Agents Chemother 1989331531ndash1534

13 Dautzenberg B Truffot C Legris S Meyohas MC Berlie HC Mercat A Chevret S Grosset J Activity of clarithromycin against Mycobacterium avium infection in patients with acquired immune deficiency syndrome Am Rev Respir Dis 1991144564ndash569

14 Chaisson RE Benson CA Dube MP Heifets LB Korvick JA Elkin S Smith T Craft JC Sattler FR Clarithromycin therapy for bacteremic Mycobacterium avium complex disease a randomized double-blind dose-ranging study in patients with AIDS Ann Intern Med 1994121905ndash911

15 Hardy DJ Swanson RN Rode RA Marsh M Shipkowitz NL Clement JJ Enhancement of the in vitro and in vivo activities of clarithromycin against Haemophilus influenzae by 14-hydroxy-clarithromycin its major metabolite in humans Antimicrob Agents Chemother 1990341407ndash1413

16 Jorgensen JH Maher LA Howell AW Activity of clari-thromycin and its principal human metabolite against Haemophilus influenzae Antimicrob Agents Chemother 1991351524ndash1526

17 Biaxin XL [package insert] North Chicago ILAbbott Laboratories 2007

18 Guay DR Gustavson LE Devcich KJ Zhang J Cao G Olson CA Pharmacokinetics and tolerability of extended-release clarithromycin Clin Ther 200123566ndash577

19 Gaete LG Schatloff OB Anziani FO Serrano CA Ceballos VN Bello PMP Ortiz MO Saavedra IS Yatabe YR Bioequivalence of two formulations of modified-release clarithromycin available in the Chilean market [in Spanish] Rev Chil Infectol 200320171ndash177

20 Cheng LK Nafziger NA Peloquin AC Amsden WG Effect of grapefruit juice on clarithromycin pharmacokinetics Antimicrobial Agents Chemo 199842927ndash929

21 Chu S Park Y Locke C Wilson DS Cavanaugh JC Drug food interaction potential of clarithromycin a new macrolide antimicrobial J Clin Pharmacol 19923232ndash36

22 Alkhalidi AB Tamimi JJ Salem II Ibrahim H Sallam IAA Assessment of the bioequivalence of two formula-tions of clarithromycin extended-release 500-mg tablets under fasting and fed conditions a single-dose ran-domized open-label two-period two-way crossover study in healthy Jordanian male volunteers Clin Therap 2008301831ndash1843

23 The United States Pharmacopeia and National FormularyndashUSP 26 NF 21 Rockville MD US Pharmacopoeial Convention 2003

24 Gurule S Verma PRP Monif T Khuroo A Partani P Sensitive liquid chromatographic determination of clarithromy-cin and 14-hydroxy clarithromycin in human plasma with

Bioavailability of single oral dose of clarithromycin 83

tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973

25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008

26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502

27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto

28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733

29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514

Page 11: Alimentos BD Claritromicina

Bioavailability of single oral dose of clarithromycin 83

tandem mass spectrometry J Liq Chromatog Relat Technol 2008312955ndash2973

25 Center for Drug Evaluation and Research US Food and Drug AdministrationGuidance for industry Bioavailability and bioequivalence studies for orally administered drug productsndashgeneral considerations Revision 1 March 2003 Available online at httpwww fdagovcderguidance5356fnlhtmaccessed September 17 2008

26 Schmidt LE Dalhoff K Food-drug interactions Drugs 2002621481ndash1502

27 Thiessen JJ Bioavailability and bioequivalence (Chapter 8) Toronto CanadaUniversity of Toronto

28 Custodio JM Wu CY Benet LZ Predicting drug disposi-tion absorptioneliminationtransporter interplay and the role of food on drug absorption Adv Drug Deliv Rev 200860717ndash733

29 Mckellars QA Brunid F Jones G Pharmacokineticpharmacodynamic relationships of antimicrobial drugs used in veterinary medicine J Vet Pharmacol Ther 200427503ndash514

Page 12: Alimentos BD Claritromicina