1 hans j roethig, philip morris usa, lsro presentation, 11, 6, 03; for discussion only clinical...

1 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only

Clinical Exposure EvaluationClinical Exposure Evaluation

Hans J. Roethig, MD, PhD, FCP, Hans J. Roethig, MD, PhD, FCP, FFPMFFPM

Director Clinical EvaluationDirector Clinical Evaluation

Philip Morris USA, Inc.Philip Morris USA, Inc.


ExposureExposure

Nicotine equivalents conceptNicotine equivalents concept

Smoking topographySmoking topography

Study designStudy design

Case studies Case studies


ExposureExposure






4

Definitions of Definitions of ExposureExposure

• Exposure is the contact over time and space Exposure is the contact over time and space

between a person and one or more between a person and one or more

biological, chemical or physical agents (US biological, chemical or physical agents (US

NRC, 1991)NRC, 1991)

• Exposure is the concentration of a substance Exposure is the concentration of a substance

in the human body over time, (c x t)in the human body over time, (c x t)

• Exposure can be measured as the area under Exposure can be measured as the area under

the concentration-time-curve, (AUC)the concentration-time-curve, (AUC)


Where Can We Determine Exposure?

Respiratory tractRespiratory tract

Central compartmentCentral compartment

TissuesTissues


ExposureExposure






Nicotine Equivalents = Molar Sum of Nicotine and its 5 Major Metabolites

N

N

CH3

HOH

O

trans-3'-hydroxycotinine

N

N

CH3

H

O

Cotinine

N

N

CH3

H

Nicotine

N

N

CH3

H

Gluc

Nicotine-N-Gluc

N

N

CH3

H

O

Gluc

Cotinine-Gluc

N

N

CH3

H

O

OGluc

trans-3'-hydroxycotinine-Gluc


Daily Nicotine Equivalents ExcretionDaily Nicotine Equivalents Excretion

Percent Change from Baseline

-120

-100

-80

-60

-40

-20

0

20

40

-1 1 2 3 4 5 6 7 8

Study Day

%Reference Cigarette 1Reference Cigarette 2EHCSSEHCSSNo Smoking


Daily Nicotine Equivalent Excretion Per Cigarette

Group Study Day

Baseline 1 3 5 8 Reference Cigarette1

1.01 (0.27)

1.15 (0.39)

1.03 (0.38)

0.96 (0.29)

1.07 (0.28)

Mean (SD)


ExposureExposure






Clinical Research Support Systems (CReSS) Clinical Research Support Systems (CReSS) Plowshares Technologies, IncPlowshares Technologies, Inc..

Lab-based CReSS


Topography Measurement CReSSTopography Measurement CReSS

Puffing ParametersPuffing Parameters

Puff Volume Puff Volume

Puff DurationPuff Duration

Inter-Puff Interval Inter-Puff Interval

Peak FlowPeak Flow

Time of Peak FlowTime of Peak Flow

Puffs per Cigarette Puffs per Cigarette

Time to First PuffTime to First Puff

Time to Removal Time to Removal

Date and TimeDate and Time


Flo

w (

ml/

sec)

»

Threshold »

Total recorded puff volume

Puff volume not recorded

Device detects start of puff >>

Device detects end

<< of puff

Puff Duration

CReSSmicro® Threshold


Source of Data Source of Data

Data from 3 clinical short term Data from 3 clinical short term

exposure studies and 1 long term exposure studies and 1 long term

study; n=363 subjects and study; n=363 subjects and

n>7260 observations of puffing n>7260 observations of puffing

parametersparameters


Relationship between Exposure and Puffing Profile

Total puff volume (TPV), total inter-Total puff volume (TPV), total inter-

puff interval (TPI) and number of puff interval (TPI) and number of

cigarettes smoked were significantly cigarettes smoked were significantly

correlated (rcorrelated (r22=0.57, p<0.001) with =0.57, p<0.001) with

nicotine equivalents nicotine equivalents per cigarette per cigarette

(NE)(NE) TPI= ∑ Inter-puff interval / Number of cigarettes


ExposureExposure






20

Reduced Exposure ClaimsReduced Exposure Claims

IOM, IOM, 20012001::

“.. For most such products the scientific evidence supporting exposure reduction claims will come from

in-vitro studies, animal studies,

and pharmacokinetic studies in humans.” (emphasis added)


CC 1

Baseline

R a

n d

o m

i z

a t i

o n

CC 1

CC 2

EHCSS

No-Smoking

Clinical Study Design: Randomized Forced-SwitchingClinical Study Design: Randomized Forced-Switching

For

ced-

switc

hing

Day - 2 Day -1 Day 1 3 8

EHCSS uncontrolled

CC 1

Acclimation


Exposure AssessmentExposure Assessment

Exposure =Exposure =

f {cigarette f {cigarette design/brand}design/brand}

x f {smoking behavior}x f {smoking behavior}

x number of cigarettesx number of cigarettes

x f {ADME of the x f {ADME of the individual}individual}

ADME = absorption, distribution, metabolism, eliminationADME = absorption, distribution, metabolism, elimination


Controlled SmokingControlled Smoking

Day –2 (before randomization):Day –2 (before randomization):

Acclimation dayAcclimation daySubjects smoking the same conventional cigarette

onlySubjects allowed to smoke as many cigarettes as

reported in their smoking history plus 20%Subjects are monitored for actual cigarette

consumption to determine their daily allotment for the remainder of the study (days -1 to 8). This determines the maximum daily allowance (6 - 30 cigarettes per day)

Smoking allowed only at predetermined smoking times from 7 AM to 11 PM (every 32 minutes, maximally 30 smoking times)

Cigarettes to be smoked evenly over the day


Daily Nicotine Equivalents ExcretionDaily Nicotine Equivalents Excretion


-120

-100

-80

-60

-40

-20

0

20

40

-1 1 2 3 4 5 6 7 8

Study Day

%Reference Cigarette 1Reference Cigarette 2EHCSSEHCSSNo Smoking


Carboxyhemoglobin (AUC)


-100

-80

-60

-40

-20

0

20

-1 1 3 8

Study Day

%

Reference Cigarette 1Reference Cigarette 2EHCSSEHCSSNo Smoking


Minimum Detectable Difference Between Study Groups In Minimum Detectable Difference Between Study Groups In Biomarkers of Exposure* (% Change from Baseline)Biomarkers of Exposure* (% Change from Baseline)

BiomarkerBiomarker VariabiliVariabili

tyty

Detectable Detectable

Difference [%]Difference [%]

Nicotine Nicotine

equivalentsequivalents

17.017.0 1515

COHbCOHb 14.014.0 1212

*Assuming 80% power, 5 % type I error rate, two-sided test, n=20 per group


Exposure AssessmentExposure Assessment

Exposure =Exposure =

f {cigarette f {cigarette design/brand} x f design/brand} x f {smoking behavior}{smoking behavior}

x x number of cigarettesnumber of cigarettes

x f {ADME of the x f {ADME of the individual}individual}

ADME = absorption, distribution, metabolism, eliminationADME = absorption, distribution, metabolism, elimination


Long Term Exposure Study Design

Continuation of Short Term Study

Unrestricted smoking, free cigarettes

Biomarkers of Exposure to be reported after 3 and 6 months


ExposureExposure




Case studiesCase studies


Case Study 1Case Study 1

Comparison of 2 cigarettes:Comparison of 2 cigarettes:

1. Reference cigarette identified1. Reference cigarette identified

2. Reference cigarette unidentified2. Reference cigarette unidentified

Same FTC tar delivery, same tasteSame FTC tar delivery, same taste


Day -1 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8

Pu

ff V

olu

me

(m

L)

20

24

28

32

36

40

44

48

52

56

60

64

68

72

76

80 Reference Cigarette IdentifiedReference Cigarette Unidentified

Mean + SD



Nic

oti

ne

Eq

uiv

ale

nts

(mg

/cig

)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

1.2

1.3

1.4

1.5

1.6Reference Cigarette IdentifiedReference Cigarette Unidentified

Mean + SD




1. Reference cigarette1. Reference cigarette

2. Test cigarette2. Test cigarette

Same FTC tar delivery, different tasteSame FTC tar delivery, different taste



Pu

ff V

olu

me

(m

L)

05

101520253035404550556065707580859095

100

Test CigaretteReference Cigarette

Mean + SD


Week

Day -1 4 12 20

Pu

ff V

olu

me

(m

L)

05

101520253035404550556065707580859095

100Test CigaretteReference Cigarette

Mean + SD



Nic

oti

ne

Eq

uiv

ale

nts

(m

g/g

Cr)

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17Test CigaretteReference Cigarette

Mean + SD




1. 2 Reference cigarettes1. 2 Reference cigarettes

2. Test cigarette2. Test cigarette

Different FTC tar delivery, different tasteDifferent FTC tar delivery, different taste


Smoking Topography

Median Puff Volume

20

40

60

80

100

120

-1 1 2 3 4 5 6 7 8

Study Day

Vo

lum

e

(ml)

Reference Cigarette 1

Reference Cigarette 2

EHCSS

EHCSS


Smoking Topography

Median Puff Duration

0

1000

2000

3000

4000

-1 1 2 3 4 5 6 7 8

Study Day

Du

rati

on

(se

c)

Reference Cigarette 1Reference Cigarette 2EHCSSEHCSS


Puffing profiles are altered Puffing profiles are altered

immediately when immediately when switchingswitching to a to a

different cigarette type but remain different cigarette type but remain

constant for the rest of the studyconstant for the rest of the study


ConclusionsConclusions

We have validated a clinical study design for the We have validated a clinical study design for the

evaluation of cigarettes concerning smoking evaluation of cigarettes concerning smoking

behavior and exposure.behavior and exposure.

Cigarettes with different FTC tar delivery and Cigarettes with different FTC tar delivery and

different taste exhibited different smoking different taste exhibited different smoking

behavior and exposure. behavior and exposure.

Based on our studies taste of cigarettes seems to Based on our studies taste of cigarettes seems to

have no influence on smoking behavior and have no influence on smoking behavior and

exposure for cigarettes with the same FTC tar exposure for cigarettes with the same FTC tar

delivery.delivery.

1 hans j roethig, philip morris usa, lsro presentation, 11, 6, 03; for discussion only clinical...

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