APPENDIX

Note. For abbreviations and explanations in Table A.I., the reader is referred to the chapter on PharmacokineticlPharmacodynarnic modeling in drug development authored by Shashank Rohatagi, Nancy E. Martin, Jeffrey S. Barrett.

529

Tab

le A

.I.

PK

lPD

Mod

els

and

Der

ived

Par

amet

ers

Use

d in

Var

ious

The

rape

utic

Are

aslD

rug

Cla

ss:

A P

arti

al L

ist.

Dru

g/C

lasS

/lndl

catlo

n(

Dos

ing

. Pha

rmac

:oki

netic

·P

O-M

odel

' -

-P~Marke?

Rtl

lmen

' P

aram

eten

1,2.

>

d-tu

bocr

arin

e (S

kele

tal

mus

cle

rela

xant

)·

Panc

uron

ium

(S

kele

tal

mus

cle

rela

xant

)

Vec

uron

ium

(S

kele

tal

mus

cle

rela

xant

)

Atra

curiu

m

(Ske

leta

l m

uscl

e re

laxa

nt

in r

enaV

hep

atic

impa

ired

patie

nts)

Dox

acur

ium

(S

kele

tal

mus

cle

rela

xant

, m

aint

ain

hem

odyn

amic

st

abili

ty

Pipe

curo

nium

Miv

acur

ium

0.5-

0.6

mgl

kg

IM,I

VQ

40-

60 m

in

0.06

-0.1

mgl

kg

IV m

aint

ain

0.01

mgl

kgQ

60

-100

min

.

O.O

S-O

.I m

glkg

IV

the

n O

.oI­

O.o

I 5 m

glkg

Q

25-4

0 m

in.

0.4-

0.5

mgl

kg

IV th

en O

.OS-

0.1

mgl

kgQ

20

-45

min

to

rela

x sk

elet

al

mus

cles

0.05

-O.0

S m

glkg

IV t

hen

0.00

05-0

.01

mgl

kgto

0.07

-O.0

S5

mgl

kg th

en

0.01

-0.0

15 Q

50

-120

min

0.15

-0.2

5 m

glkg

IV

bol

us

then

0.1

mgl

kg

Q 1

5 m

in.

Vd: 0

.39±

O.1

4lJk

g C

L: 1

.9t 0

.6 m

Um

inlk

g T

,ll:

2.0±

I.I

h

V.:

0.26

iO.0

7 lJ

kg

CL:

I.S

iO.4

mU

min

lkg

Vd: 0

.2IiO

.OS

lJkg

C

L: 3

.0±0

.1 m

Um

inlk

g

V d:

O.l6

iO.0

6lJk

g C

L: 6

.2±2

.0 m

Um

inlk

g

Vd: 0

.35i

O.O

S C

L: [

jkg

2.1

iO.5

mU

min

lkg

Ane

sthe

tlcs:

Neu

rom

uscu

lar

Blo

ckin

g A

gent

s In

dire

ct L

ink

Sigm

oid

Ner

omus

cula

r bl

ock

E,..

, Mod

el

% M

uscu

lar

Para

lysi

s

Indi

rect

Lin

k Si

gmoi

d E

,..,M

odel

Indi

rect

Lin

k Si

gmoi

d E

,..,M

odel

Indi

rect

Lin

k Si

gmoi

d E

,..,M

odel

Indi

rect

Lin

k Si

gmoi

d E

,..,M

odel

Indi

rect

Lin

k Si

gmoi

d E

,..,M

odel

Indi

rect

Lin

k Si

gmoi

d E

max

Mod

el

Ner

omus

cula

r bl

ock

% M

uscu

lar

Para

lysi

s

Ner

omus

cula

r bl

ock

% M

uscu

lar

Para

lysi

s

Ner

omus

cula

r bl

ock

% M

uscu

lar

Para

lysi

s

Ner

omus

cula

r bl

ock

% M

uscu

lar

Para

lysi

s

Ner

omus

cula

r blo

ck

% M

uscu

lar

Para

lysi

s

Ner

omus

cula

r bl

ock

% M

uscu

lar

Para

lysi

s

Phar

mac

odyn

amic

P

aram

eten

E.. ..

: 100

"10

E,.,

0.6O

±O.2

2 m

cg/m

L

N:

-T

'IlK

e0=

4.7t

I.2

min

E..,

: 10

0"10

E

,.,O

.2IiO

.OS

mcg

/mL

N

: 5.4

Stl

.64

T,IlK

eo:

1.43

min

E,..

,: 10

0"10

E

,.,O

.lIiO

.02m

cg/m

L

N: -

T,"

Keo

: 6.

1 m

in

E...:

100%

E

,.,0.

24iO

.04m

cg/m

L

N: 3

.4iO

.37

T,IlK

eo: 5

.1 m

in

E..,

: 10

0"10

E

,. 34

.9t1

2.0

ng/m

L

N: 3

.3iO

.7

T'Il

Keo

=I0.

7±4.

4 m

in

E,. .

. : 1

00"1

0 E

,.6

3 n

g/m

L

N: -

T,,,

Keo

: -

E,..

,: 10

0%

E",

67.

3±30

.4 n

g/m

L

N: 4

.4t1

.3

T,,,

Keo

: 4.

9t2.

3 m

in

I.

Lacy

CF,

Ann

stro

ng L

L, G

oldm

an M

P, L

ance

LL.

D

rug

info

rmat

ion

hand

book

. 19

99-2

000.

2.

H

ardm

an J

G, L

imba

rd L

E, G

ilman

AG

. Th

e ph

arm

acol

ogic

al b

asis

of t

hera

peut

ics.

10

· edi

tion,

McG

raw

Hill

, New

Yor

k.

2001

. 3.

D

eren

dorf

H a

nd H

ochh

aus

G.

Han

dboo

k of

pha

rmac

okin

etic

lpha

rmac

odyn

amic

cor

rela

tion.

CR

C P

ress

, Boc

a R

aton

, 199

5.

Ref

eren

ces

Stan

ski

DR

, Ham

J, M

iller

RD

, She

iner

LB

. Ph

arm

acok

inet

ics

and

phar

mac

odyn

amic

s of

d­tu

bocu

rarin

ne in

man

. A

nest

hesi

olog

y 19

72: 3

6: 2

13.

Evan

s M

A, S

hank

s C

A, B

row

n K

F, T

riggs

EJ.

Phar

mac

okin

etic

s an

d ph

arm

acod

ynam

ic m

odel

ing

with

pan

curo

nium

. Eu

r J C

lin P

harm

acol

. 19

84: 2

6:

243.

Sohn

YJ,

Ben

cini

AF,

Sca

f AH

J, K

erst

en U

W,

Ago

ston

S.

Com

para

tive

phar

mac

okin

etic

s an

d dy

nam

ics

ofve

curo

nium

and

pan

curo

nium

in

anae

sthe

tized

pat

ient

s. A

nest

h A

nalg

198

6: 6

5: 2

33.

Don

ati

F, V

arin

F, D

ucha

rme

J, G

ill S

S, T

heor

et Y

, B

evan

DR

. Ph

arm

acok

inet

ics

and

phar

mac

odyn

amic

s of

atra

curiu

m o

btai

ned

with

arte

rial a

nd v

enou

s bl

ood

sam

ples

. C

lin P

harm

acol

The

r 19

91: 4

9: 5

15.

Schm

idt V

D, L

ai A

, Dre

ssne

r DL,

Bas

ta S

J, Ja

mes

CD

, W

argi

n W

A, S

avar

ese

JJ.

Phar

mac

odyn

amic

mod

elin

g o

f dox

acur

ium

in y

oung

adu

lt an

d el

derly

pat

ient

s.

Phar

Res

199

1: S

: S-2

76.

Orn

stei

n E,

Mat

teo

RS,

Sch

war

tz A

E, J

amda

r SC

, Dia

z J.

Phar

mac

okin

etic

s an

d ph

arm

acod

ynam

ics

of

pipe

curiu

m b

rom

ide

(Ard

uan)

in e

lder

ly s

urgi

cal

patie

nt

Phill

ips

L, S

chm

idt V

D, L

ien

CA

, Em

bree

PB

, Jam

es

CD

, Lai

A,

Sava

rese

JJ.

M

ivac

uriu

m s

teri

oiso

mer

ph

arm

acod

ynam

ic ...

Ph

arm

Res

199

2: 9

: S-3

56.

~ > :: l"l

2!

t:I ><

Dru

glC

I.,s

Ilnd

l •• t

ion '

D

o,ln

g P

harm

a.ok

inet

l.

PO-M

oder

' P

O-M

arke

r'

Riv

astig

min

e

Ace

tam

inop

hen-

ibup

rofe

n-

Fent

anyl

(an

esth

etic

)

Alfe

ntan

il (a

nest

hetic

)

Sufe

ntan

il (f

or a

nalg

isia

la

nest

hetic

)

Reg

imen

1 P

aram

ctcr

sl.1

.J

1-6m

gpoB

ID

12.5

mgl

leg

po

5-\0

ngl

leg

po

0.5-

1.0

meg

llegl

dose

1M

, IV

; 25

meg

lh

trans

derm

al

8-40

meg

lleg

IV

1-2m

eglle

g IV

an

d 10

-25

meg

pm

F: 2

2-11

9"10

Y

.: 23

6 L

C

L: 1

26lJ

hr

F: 8

8"10

V

.: 0.

15 i

O.0

2 U

kg

CL:

0.7

5iO

.2 m

Um

inlk

g T,

ll: 2

.0±0

.5 h

F: 8

0"10

Y

,: 0.

95 i

O.l2

Ukg

C

L: 5

.OtI

.4 m

Um

inlk

g T,

ll: 2

.0±0

.4 h

Y.:

4.0±

0.4

Ukg

C

L: 1

3±2

mU

min

lkg

Y.:

0.8i

O.3

Ukg

C

L: 6

.7±2

.4 m

Um

inlk

g

Y.:

1.7i

O.6

Ukg

C

L: 1

2.7±

2.5

mU

min

lkg

Cho

line

ster

ase

Inbl

blto

n Si

gmoi

d E

... M

odel

C

ogni

tive

chan

ge

(mea

sure

d by

the

Com

pute

rised

N

euro

psyc

holo

gica

l Te

st B

atte

ry i.

e C

NT

Bsc

ore

Ant

ipyr

etic

s Si

gmoi

d E

... M

odel

N

erom

uscu

lar b

lock

"10

Mus

cula

r Par

alys

is

Sigm

oid

E..

. Mod

el

Ner

omus

cula

r blo

ck

"10 M

uscu

lar P

aral

ysis

Opl

old

Ane

sthe

tics

In

dire

ct L

ink

Sigm

oid

Elec

troen

c:eph

alogn

m

E.. ..

Mod

el

(EEG

)

Indi

rect

Lin

k Si

gmoi

d E

"..M

odel

Indi

rect

Lin

k Si

gmoi

d E

...M

odel

E1ec

troen

eeph

alog

nm

(EEG

)

Elec

troen

ceph

alog

nm

(EEG

)

Pba

rmac

odyn

lmk

Par

amet

ers

E...

:lOO

"lo

E ..

,5.4

2 m

e&'L

N

=O.5

sco

re/y

ear

E ..

, 4.6

3± 0

.39

meg

lmL

E..

I 1.3

3± 1

.35

meg

lmL

E,..

.: 14

.1±1

.8 H

z E

,. 6.

9±1.

5 ng

lmL

N: 4

.9±1

.0

T'Il

Keo

=6.4

±1.3

min

Eo

: 19.

2±1.

6 H

z

Em .. :

14.

7±3.

l H

z E

,., 5

20t 1

63 n

glm

L N

: 4.8

±1.5

T

'IlK

eo=l

.IiO

.3m

in

Eo: 2

0.1±

3.4

Hz

Em .. :

14.

7±3.

1 H

z E

,.,0.

68iO

.31

nglm

L N:

3.1

±.09

T

'IlK

eo=6

.2±2

.8m

in

Eo: 2

4.3±

2.7

Hz

Ref

eren

ces

Gob

buru

NS

, Tam

mar

a Y

, et a

l. Ph

arm

acok

inet

ic­

Phar

mac

odyn

amic

Mod

elin

g of

Riv

astig

min

e, a

C

holin

este

rase

Inhi

bito

r, in

Pat

ient

s w

ith A

lzhe

imer

's D

isea

se.

J C

lin P

harm

acol

200

1;41

: I 08

2-1 0

90.

Bro

wn

RD

, et a

l. In

tegr

ated

pha

rmac

okin

etic

­ph

arm

acod

ynam

ic m

odel

for

ace

tam

inop

hen,

ib

upro

fen,

and

pla

cebo

ant

ipyr

esis

in c

hild

ren.

J

Phar

mac

okin

et B

ioph

arm

. 19

98 O

ct;2

6(5)

:559

-79.

Bro

wn

RD, e

t al.

Inte

grat

ed p

harm

acok

inet

ic­

phar

mac

odyn

amic

mod

el f

or a

ceta

min

ophe

n,

ibup

rofe

n, a

nd p

lace

bo a

ntip

yres

is in

chi

ldre

n. J

Ph

arm

acok

inet

Bio

phar

m.

1998

Oct

;26(

5):5

59-7

9.

Scot

t JC

, Pon

gani

s K

Y, S

tans

ki D

R.

EEG

Q

uant

ifica

tion

of na

rcot

ic e

ffec

t: th

e co

mpa

rativ

e ph

arm

acod

ynam

ic e

ffec

t of f

enta

nyl a

nd a

lfent

anil.

A

nest

hesi

olog

y 19

91: 7

4: 3

4.

Scot

t JC

, Pon

gani

s K

Y, S

tans

ki D

R. E

EG

Qua

ntifi

catio

n of

narc

otic

eff

ect:

the

com

para

tive

phar

mac

odyn

amic

eff

ect o

f fen

tany

l and

alfe

ntan

il.

Ane

sthe

siol

ogy

1985

: 62:

.

Scot

t JC

, Coo

ke J

C, S

tans

ki D

R.

Ele

ctro

ence

phal

ogra

phic

qua

ntifi

catio

n of

opio

id

effe

ct:

com

para

tive

phar

mac

odyn

amic

eff

ect o

f fe

ntan

yl a

nd s

ufen

/&ni

l. A

nest

hesi

olog

y 19

91: 7

4: 3

4.

>

."

~ :2 ~ ~ ...

Dru

g/C

lass

llnd

i<at

ion'

--D

osin

g Ph

arm

acok

inet

ic

Reg

imen

l P

aram

eter

sl.l.

l

Dia

zepa

m (

anxi

ety,

2-

10 m

g p.

o. 2

-F:

100

"10

seda

tion,

or

mus

cle

4 tim

es/d

ay, 2

-V

,: l.

ltO

J U

kg

rela

xatio

n)

10m

g1M

, IV

C

L: 0

.38t

O.0

6 m

Um

inlk

g Q

3-4h

or 5

-10

mg

IV Q

10-

20

min

, up

to 3

0 m

g/8h

Mid

azol

am (

seda

tion)

P

reop

erat

ive

F:44

%

seda

tion:

0.0

7-V

,: I.

ltO

.06

Ukg

0.

08 m

g/kg

1M

C

L: 6

.6±1

.8 m

Um

inlk

g or

0.0

2-0.

04

mg/

kg I

V Q

5

min

. up

to

0.I-

O.2

mg/

kg

Oxa

zepa

m

10-3

0 m

g po

F:

100

%

q6h

Fb: 8

6-99

%

Tl/

2: 2

.8-5

.7 h

Lor

azep

am

2t0

4m

gp

o

Fb:

88-9

2%

daily

V

,: 1.

3 U

kg

Tl/

2:

10-2

0 h

PD-M

odel

' P

D-M

arke

r'

Ben

zodi

azel

!ine

s-se

dativ

es, a

ntic

onvu

lsan

ts

Sigm

oid

E""

,Mod

el

SA

-lV

: ap

erio

dic

sign

al

PSA

b: P

ower

sp

ectru

m a

naly

sis

of

alph

a w

aves

Indi

rect

Lin

k Si

gmoi

d S

A-l

V: a

perio

dic

E,.

" M

odel

si

gnal

.

Indi

rect

Lin

k Si

gmoi

d SA

-TN

W: a

perio

dic

E,."

Mod

el

sign

al a

naly

sis

of

tota

l num

ber o

f w

aves

.

Sigm

oid

E"",

Mod

el

PSA

-b: p

ower

sp

ectru

m a

naly

sis

of

beta

-wav

es

Sigm

oid

E"",

Mod

el

Ant

icon

vuls

ant

in th

e PT

Zm

odel

Sigm

oid

E"",

Mod

el

CN

S im

pairm

ent

mea

sure

d by

co

mpu

teriz

ed

track

ing

syst

em

(TR

KN

)

Phar

mac

odyn

amic

P

aram

eter

s

E,.,

,: 13

4±57

E

", 9

58±2

oo n

glm

L

N:

J.6±

.0.6

T

II,K

eo=J

.6tO

.5 m

in

E0:

39±

17

E,.,

,: 20

.2%

E

,., 2

70 n

glm

L

N:2

.1

E"",

: 12

5±13

E

,., 1

52±4

8 ng

lmL

N

: 1.

9±.0

.2

T,12

Ke0

=4.8

±1.5

min

Eo

: 40±

18

E"",

: 9.7

±1.5

E

,., 2

90±9

8 ng

lmL

N

: 3.

1±.1

.0

T'I2

Kco

=1.7

tO.7

min

Eo

: 0.7

±0.

3

E,..

,: 22

.4%

EC

,., 3

5 ng

lmL

N

: 2.2

EC

",

99

± 1

9n9l

mL

R

ecep

tor

bind

ing

to

GA

BA

: 86

± 1

5 ng

/mL

E,.,

,: 41

8 E

C,.

35.8

ngl

mL

N

: 6.2

9 T

II,K

eo=O

.43

h

Ref

eren

ces

Buh

rer M

, Mai

tre P

O, C

revo

isie

r C, S

tans

ki D

R.

Ele

ctro

ence

phal

ogra

phic

eff

ects

of b

enzo

diad

epin

es n

. Ph

arm

acod

ynam

ic m

odel

ing

of th

e el

ectro

ence

phal

ogra

phic

eff

ects

of m

idaz

olam

and

di

azep

am. C

lin P

harm

acol

The

r 19

90: 4

8: 5

55.

Gre

enbl

att O

J, E

hren

berg

BL,

Gun

derm

an J

, Loc

nisk

ar

A, S

cavo

ne J

M, H

anna

tz J

S, S

hade

r RI

. Ph

arm

acok

inet

ic a

nd e

ncep

halo

grap

hic

stud

y of

in

trave

nous

dia

zepa

m, m

idaz

olam

and

pla

cebo

. C

lin

Phar

mac

ol T

her

1989

: 45:

356

.

Phar

mac

okin

etic

and

enc

epha

logr

aphi

c st

udy

of

intra

veno

us d

iaze

pam

, mid

azol

am a

nd p

lace

bo.

Clin

Ph

arm

acol

The

r 19

89: 4

5: 3

56.

Brie

rncr

LTM

, Hen

nis

PJ, B

urm

AG

L, D

anho

fM,

Bov

ill J

G, S

pier

dijk

J, V

lette

r A

A.

Qua

ntifi

catio

n of

th

e EE

G e

ffec

t of m

idaz

olam

by

aper

iodi

c an

alys

is in

vo

lunt

eers

: ph

arm

acok

inet

iclp

harm

acod

ynam

ic

mod

elin

g. C

lin P

harm

acok

inet

199

0: 1

8: 2

45.

Gre

enbl

att O

J, E

hren

berg

BL,

Gun

derm

an J

, Loc

nisk

ar

A, S

cavo

ne J

M, H

arm

atz

JS, S

hade

r RI

. Ph

arm

acok

inet

ic a

nd e

ncep

halo

grap

hic

stud

y of

in

trave

nous

dia

zepa

m, m

idaz

olam

and

pla

cebo

. C

lin

Phar

mac

ol T

her

1989

: 45:

356

.

Man

dem

a JW

, San

som

LN

, Dio

s-V

ieite

z, M

C,

Hol

land

er-J

anse

n M

, and

Dan

hof M

. Pha

rmac

okin

etic

­ph

arm

acod

ynam

ic m

odel

ing

of th

e EE

G e

ffec

ts o

f b

enzo

dia

zep

ines

. C

orre

lati

on w

ith

rece

ptor

bin

din

g an

d w

ith a

ntic

onvu

lsan

t act

ivity

. J P

harm

acol

Exp

The

r 19

91: 2

57: 4

72.

Gup

ta S

I(, E

llenw

ood

EH, N

ikai

do A

M, H

eath

erly

0

0.

Sim

ulta

neou

s m

odel

ing

of th

e ph

arm

acok

inet

ic

and

phar

mac

odyn

amic

pro

perti

es o

fben

zodi

azep

ines

I.

Lor

azep

am. J

Pha

rmac

okin

et B

ioph

arm

199

0: 1

8: 8

9.

~

N > ~ 2 t:l ><

>

DruglClassllndication~oslng

Phar

mac

okln

etic

PD

-Mod

et'

PD-M

arke

l"

Phar

mac

odyn

amic

R

efer

ence

s ::

Reg

imen

' P

aram

eter

s''''

' P

aram

eten

l!I!J

:z T

riaz

olam

0.125~.25mg

Fb: 8

9-94

%

Sigm

oid

E..

. Mod

el

CN

S im

pairm

ent

EC5O

. 4.6

5 ng

lmL

Sm

ith R

B, K

robo

th P

O, V

arne

r PD

. 1:1

po

dai

ly

V.:

0.8-

1.3

Ukg

m

easu

red

by D

SS

Phar

mac

odyn

amic

s of

tria

zola

m a

fter

intra

veno

us

- >< T

l/2:

2.3

h

(psy

chom

otor

ad

min

istra

tion.

J C

lin P

harm

acol

198

7: 2

7: 9

71.

perf

orm

ance

) tes

t sc

ore

Alp

razo

lam

0.

25-l

mg

Fb: 8

0%

Sigm

oid

E..

. Mod

el

CN

S im

pairm

ent

EC

5O.lO

nglm

L

Schm

ith V

D, P

irain

o B

, Sm

ith R

B, K

robo

th P

D.

po T

ID

V.:

1.1

Ukg

m

easu

red

by D

SS

Alp

razo

lam

in e

nd s

tage

rena

l dis

ease

II.

Tl/

2: 1

2-15

h

(psy

chom

otor

Ph

arm

acod

ynam

ics,

Clin

Pha

rmac

ol T

her

1992

: 5 I:

pe

rfor

man

ce) t

est

533.

sc

ore

Flum

azen

il 0.

2 m

g/kg

ove

r F

:80%

C

ompe

titiv

e an

tago

nist

EE

G

E50

Mid

azol

am :

30

Man

dem

a JW

, Tuk

ker

Eo D

anho

f M.

In v

ivo

(ben

zodi

azep

ine

IS s

ec. w

ith

V.:

0.95

Ukg

of

M id

azol

am u

sing

ng

lrnL

ch

arac

teriz

atio

n of

phar

mac

odyn

amic

inte

ract

ion

of a

an

tago

nist

) m

axim

um

CL:

hig

h ba

sed

on l

iver

E

,."

mod

el

E50

flum

azen

il: 2

6 ng

lml

benz

odia

zepi

ne a

goni

st a

nd a

ntag

onis

t: m

idaz

olam

and

cu

mul

ativ

e bl

ood

flow

bu

t has

no

effe

ct o

n flu

maz

enil.

J

Phar

mac

ol E

xp T

her

1992

: 260

: 36.

d

ose

ofl

mg

T'll

: 241

-79

min

E

EG

alon

e A

ntic

onvu

lsan

t all

!nts

Ph

enob

arbi

tal

30-1

20m

gpo

F: 1

00 ±

11%

Si

gmoi

d E

...M

odel

A

ntic

onvu

lsan

t PTZ

E

...:

120m

glL

ofP

TZ

D

inge

man

se J

, Van

Bre

e JB

MM

and

Dan

hof M

. da

ily in

2-3

Fb

:51

±3%

m

odel

EC

50 (f

ree)

: 44

± 5

mgI

L Ph

arm

acok

inet

ic m

odel

ing

of an

ticon

vuls

ant r

espo

nse

divi

ded

dose

s V

.: 0.

54 ±

0.0

3 U

kg

(pen

tyle

nete

trazo

l of

Phe

noba

rbita

l in

rat

s. J

Pha

rmac

ol E

xp T

her

1989

: C

L: 0

.062

± 0

.013

th

resh

old

249:

601

m

l/min

lkg

conc

entra

tion)

T,n

:99

± 1

8h

Ane

sthe

tic a

sent

s Pr

opof

ol (

seda

tive,

gen

eral

2-

2.5

mg/

kg iv

V

.: 1.

7±O

.7 U

kg

E..

Mod

el

% o

f pat

ient

s th

at

EC5O

: 0.9

5-1.

07

Vuy

k J,

Eng

bers

FH

M, L

emm

ons

HJM

, Bur

m H

GL,

an

esth

etic

) un

til o

nset

of

CL:

276

±S m

Um

inlk

g w

ere

awak

e af

ter

mcg

lmL

V

Iette

r A

A, G

ladi

nes

MPR

R, B

ovil

JG.

indu

ctio

n T,

n: 3

.5t1

.2 h

su

rger

y Ph

arm

acod

ynam

ics

of pr

opof

ol in

fem

al p

atie

nts.

A

nest

hesi

olog

y 19

92: 7

7: 3

. Fi

xed

Eff

ect

adeq

uate

ane

sthe

sia

Shaf

er A

, Doz

e V

A, S

hafe

r SL,

Whi

te P

F.

for s

urge

ry

Mea

n C

once

ntra

tions

> Ph

arm

acok

inet

ics

and

phar

mac

odyn

amic

s of

prop

ofol

4.

01 m

cglm

L fo

r m

ajor

in

fusi

ons

durin

g ge

nera

l ane

sthe

sia.

Ane

sthi

logy

su

rger

y an

d> 2

.97

1988

: 69:

348

. m

cglm

L f

or n

on-m

ajor

su

rger

y

Etom

idat

e (g

ener

al

0.2-

0.6

mg/

kg

F.: 7

6%

Inhi

bito

ry S

igm

oid

Med

ian

freq

uenc

y El

O: t

hiop

enta

lnO

A

rden

JR

, Hol

ley

FO, S

tans

ki D

R, E

blin

g W

F.

Dos

e an

esth

esia

, hyn

otic

) ov

er 3

0-60

sec

. V

.: 3.

6-4.

5 U

kg

E..-

Mod

el

calc

ulat

ed f

rom

po

tenc

y co

mpa

rison

of t

hiop

enta

l an

d st

omid

ate.

T,

~: 2

.6 h

sp

ectra

l ana

lysi

s of

A

nest

hesi

olog

y 19

85: 6

3: A

286.

EE

G

Ket

amin

e (R

,S)

(gen

eral

1-

4.5

mg/

kg iv

In

hibi

tory

Sig

moi

d M

edia

n fr

eque

ncy

E5O:

(R

-):

1.8

mcg

lmL

Sc

huttl

er J,

Sta

nski

DR

, Whi

te P

F, T

revo

r A

J, H

orai

Y,

anes

thes

ia, h

ynot

ic)

or 3

-8 m

g/kg

E

.a-M

odel

ca

lcul

ated

fro

m

ElO:

(S+

): 0.

8 m

cglm

L

Ver

ona

0, S

hein

er L

B.

Phar

mac

odyn

amic

mod

elin

g im

in a

dults

or

spec

tral a

naly

sis

of

ElO:

(R

,S):

2.0

mcg

lmL

of

the

EEG

eff

ects

of k

etam

ine

and

its e

nant

iom

ers

in

6-10

mg/

kg o

ral

EEG

E

.. w

as d

iffer

ent f

or

man

. J

Phar

mac

okin

et B

ioph

arm

198

7: 7

1: 3

34.

in c

hild

ren,

th

e th

ree

anal

yles

U

I \0

0 \0

0

Dru

g/C

lass

/Ind

icat

ion'

D

osin

g P

harm

acok

inet

ic

PO

-Mod

el'

-P

D-M

ark

e7

Reg

imen

' P

aram

eter

s',l,

3

Mor

phin

e (a

nalg

esia

)

Met

hado

ne (

anal

gesi

a)

Ket

obem

idon

e (a

nalg

esia

)

15-3

Om

gPO

ev

ery

8-I 2

h; 1

0 m

g/do

se 1

M,

IV, S

C e

very

4h

; 0.8

-IO

mg/

h IV

cont

. in

fusi

on; 5

mg

epid

ural

up

to

IOm

g/24

h; 1

0-20

mgr

ccta

l ev

ery4

h

Ana

lges

ia:

2.S-

10 m

g PO

, 1M

, SC

eve

ry 3

-8h;

D

etox

ifica

tion:

IS

-4O

mgl

day

PO;

Opi

ate

depe

nden

ce:

20-1

20m

glda

y

F: 2

4±12

%

Fb: 3

S±2%

V

.: 3.

3±O

.9 U

kg

CL:

24±

10 m

Um

inlk

g T'

I2:

1.9±

O.S

h

F: 9

2±21

%

Fb: 8

9±2.

9"1o

V

.: 3.

6±1.

2Ukg

C

L: 2

.3±1

.2 m

Um

inlk

g T

",:

27±1

2 h

Opl

old

Ana

lges

ics

Log

istic

lPro

bit a

naly

sis

Cum

ulat

ive

Fixe

d E

ffec

t

Log

istic

lPro

bit a

naly

sis

Fixe

d E

ffec

t

Log

istic

lPro

bit a

naly

sis

Fixe

d E

ffec

t

freq

uenc

y o

f pat

ient

s at

tain

ing

com

fort

scor

e of

2.

Mea

n ef

fect

co

ncen

tratio

n (M

EC

) w

hich

is th

e co

ncen

tratio

n at

the

time

rem

edic

atio

n is

requ

ired.

Cum

ulat

ive

freq

uenc

y of

pat

ient

s at

tain

ing

com

fort

sc

ore

of2.

Mea

n ef

fect

co

ncen

tratio

n (M

EC

) w

hich

is th

e co

ncen

tratio

n at

the

time

rem

edic

atio

n is

re

quire

d.

Cum

ulat

ive

freq

uenc

y of

patie

nts

atta

inin

g co

mfo

rt sc

ore

of2.

Mea

n ef

fect

co

ncen

tratio

n (M

EC

) w

hich

is th

e co

ncen

tratio

n at

the

time

rem

edic

atio

n is

re

quire

d.

Pha

rmac

odyn

amic

P

aram

eten

E,.:

12.S

-i3.

1 ng

lmL

N

: 3.6

4-6.

89

MEC

: IS

±5 n

glm

L

E,.:

SO.

4 ng

lmL

N

:4.2

8

MEC

: S9±

24 n

glm

L

E,.:

22.

S ng

lmL

N

:4.6

4

MEC

: 2S

±11

nglm

L

Ref

eren

ces

Gou

rlay

GK

, Will

is R

J, La

mbe

rty J

. A

dou

ble-

blin

d co

mpa

rison

of t

he e

ffic

acy

of m

etha

done

and

mor

phin

e in

pos

tope

rativ

e pa

in c

ontro

l. A

nest

hesi

olog

y 19

86:

64: 3

22.

Dah

lstro

m B

, Tam

sen

A, P

aalz

ow L

, H

artv

ig P

. Pa

tient

con

trolle

d an

alge

sic

ther

apy

III.

Phar

mac

okin

etic

s an

d an

alge

sic

plas

ma

conc

entra

tions

of

mor

phin

e. C

lin P

harm

acok

inet

19

82: 2

66: 7

.

Dah

lstro

m B

, Tam

sen

A, P

aalz

ow L

, H

artv

ig P

. Pa

tient

con

trolle

d an

alge

sic

ther

apy

III.

Ph

arm

acok

inet

ics

and

anal

gesi

c pl

asm

a co

ncen

tratio

ns

of m

orph

ine.

Clin

Pha

rmac

okin

et 1

982:

266

: 7.

Tam

sen

A, B

onde

sson

U, D

ahls

trom

B, H

artv

ig P

. Pa

tient

-con

trol1

ed a

nalg

esic

the

rapy

III.

Ph

arm

acok

ient

ics

and

anal

gesi

c pl

asm

a co

ncen

tratio

ns

of ke

to m

id on

e. C

lin P

harm

acok

inet

ic

1982

: 266

: 7.

~ >

~

~

l'"l Z

I:' ><

Dru

g/C

lass

/Ind

icat

ion'

D

osin

g Ph

arm

acok

inet

lc

PO-M

odet

' PO

-Mar

!<e?

R

etllm

en'

P.r

.m.t

ers'

....

Ph.

rm.c

odyn

.mlc

P

.ram

eter

s M

eper

idin

e (a

nalg

esia

)

Hyd

rom

orph

one

(ana

lges

ic, a

ntitu

ssiv

e)

Ace

tam

inop

hen

Asp

irin

Indo

met

haci

n

50-I

SO m

gldo

se

F: 5

2:1:

3%

PO,I

M, I

V, S

C

F.:

58±9

%

ever

y 3-

4 ho

urs

V.:

4.4i

O.9

Ukg

l-4m

gQ4-

6h

po, i

m, i

v sc

, pm

325-

500

mg

po

q6

h;u

pto

4

iVda

y

325-

6SO

mg

po

q4

-6h

up

to4

iV

daily

0.2

mlfk

g in

ne

onat

es f

or

pate

nt d

uctu

s ar

terio

sus

CL:

17±

S m

Um

inlk

g T

1/2: 3

.W.8

h

F: 4

2±23

%

F.: 7

.1%

V

.: 2.

9O±1

.31

Ukg

C

L: 1

4.6±

7.6

mU

min

lkg

T'I2

: 2.4

iO.6

h

F: 8

8±15

%

F.:

20%

V

.: 0.

95±

O.l2

Ukg

C

L: 5

.Ot1

.4 m

Um

inlk

g T'

I2: 2

.0i0

.4 h

F: 6

8 ±

3%

F.: 4

9%

V.:

0.15

iO.0

3 U

kg

CL:

9 .3

± t.

t m

Um

inlk

g T

,12:

0.2

5iO

.03

h

F: 9

8±21

%

F.: 9

0%

V.:

0.29

±O.0

4 U

kg

CL

:I.4

± 0

.2m

Um

inlk

g T'

I2: 2

.4iO

.2 h

Log

istic

lPro

bit a

naly

sis

Fixe

d E

ffec

t

Fixe

d E

ffec

t

Cum

ulat

ive

freq

uenc

y o

f pat

ient

s at

tsin

ing

com

fort

scor

eof2

.

Mea

n ef

fect

co

ncen

ttatio

o (M

EC)

whi

ch is

the

conc

entta

tion

at th

e tim

e re

med

icat

ioo

is

requ

ired.

Pain

Coo

trol

Non

oplo

ld A

na1&

es1e

s E

".-U

nk M

odel

P

.in c

ootro

V

Ana

lges

ia

E ..

: 253

niV

mL

N:4

.3.8

MEC

: 3II

±18

8 nW

mI-

Hyd

rom

orph

one

conc

entta

tions

> 4

niV

mL

prov

ided

goo

d pa

in c

ootro

l in

pat

ient

s w

ith b

one

or s

oft t

issu

e in

jury

but

not

eff

ectiv

e in

neu

ropa

thic

pai

n.

EC

,., 1

34-2

67 m

ciV

mL

T, 12

Keo

-7-1

3 m

in

Non

st.r

olda

l Ant

i-ln

O.m

m.to

ry D

roll

-An.

lges

lc e

ffec

ts

Sigm

oid

E".

-Unk

Pa

in m

odel

with

third

E

".:

100%

M

odel

m

olar

sur

gery

E

C,.,

5.3

mci

Vm

L N

: 1.

35

T,1

2Kco

=20

min

Fixe

d E

ffec

t Pa

tenc

y of

duct

us

arte

riosu

s E

ffec

t see

n in

neo

nate

at

conc

entta

tions

abo

ve

200

mcg

lI.;

No

corr

elat

ion

for

anal

gesi

a

Ref

eren

ces

Gly

nn C

J, M

.ther

LE,

Cou

sins

MJ,

Gra

ham

JR

, W

illon

PRo

Per

idur

al m

eper

idin

e in

hum

ans:

ana

lget

ic

resp

onse

, pha

rmac

okin

etic

s an

d tta

nsm

issi

oo i

nto

CSF

. A

nest

hesi

olog

y 19

81: 5

5: 5

20.

Rci

denb

erg

MM

, Goo

dman

H, e

rIe

H, G

ray

G,

Lore

nzo

B, L

eipz

ig R

M, M

eyer

BR

, Dra

yer D

E.

Hyd

rom

orph

one

leve

ls a

nd p

ain

cont

rol i

n pa

tient

s w

ith s

ever

e ch

roni

c pa

in.

Clin

Pha

nnac

ol T

hor

1988

: 44

: 376

.

Col

burn

W A. S

imul

tane

ous

phan

naco

kine

tic a

nd

phan

naco

dyna

mic

mod

elin

g. J

Pha

nnac

okin

et

Bio

pila

nnI9

81:9

:367

.

Vcl

agap

udi R

, Har

ter J

C, B

ruec

ker R

, Pec

k C

C.

Phar

mac

okin

etic

pha

nnac

odyn

amic

mod

els

in

anal

gesi

c st

udy

desi

gn, i

n ad

vanc

es in

pai

n re

sear

ch

and

ther

apy.

Vol

18.

MIX

M, P

orte

noy

R, a

nd L

aska

E,

Eds.

Rav

en P

ress

, New

Yor

k 19

91,5

59.

Bcr

ash

A, H

icke

y D

, Gra

ham

T, S

tahl

am M

, Oat

es J

, an

d C

otto

n R

B. P

hann

acok

inet

ics

of in

dom

etha

cin

in

the

neon

ate:

rel

atio

n o

f pla

sma

indo

niet

haci

n le

vels

to

resp

onse

of d

uctu

s ar

terio

sus.

N E

ng J

Med

19

81:3

05:6

7.

~ ~ ~

Dru

g/C

I .. S

/indi

catio

n'

Dos

ing

Pha

rmac

okln

etic

I'D

-Mod

el'

. PD

-Mar

ker'

R

egim

en'

Par

amet

ers'

''''

Ibup

rofe

n 40

0-80

0 m

g po

F:

80"

..1.

E...

-Mod

el

Pain

rel

ief a

fter

Flur

bipr

ofen

Tol

men

tin

Sele

gilin

e

tid o

r qid

with

F.

: 99%

de

ntal

sur

gery

m

axim

um d

ose

Y.:

0.IS

:tO.0

2 ()

kg

of 3

.2 g

/d

CL

: 0.

7S:tO

.20

mU

min

lkg

200-

300

mgl

day

po in

2,

3, o

r 4 d

ivid

ed

dose

s

60

0-1

80

0 m

g po

dai

ly in

di

vide

d do

ses

5 m

gpo

twic

e da

ily a

t br

eakf

ast a

nd

lunc

h

T,"

: 2

±O

.S h

F:9

2%

F.:

99.5

%

Y.:

O.lS

± 0.

02()

kg

CL

: 0.3

S± O

.09m

Um

inlk

g T

,":

S.S±

1.4

h

F.:

99%

T

,":

Sh

F: n

eglig

ible

F.

: 94

%

Y.:

1.9

()kg

C

L:

ISO

Om

Um

inlk

g T

,":

1.9

± 1

.0 h

E.. ..

-Mod

el w

ith t

ime

dela

y (T

..,)

E.. ..

-Mod

el w

ith t

ime

dela

y {T

,..>

No

mod

el i

dent

ifie

d

Ant

iinfl

amm

ator

y ef

fect

link

ed w

ith

plat

elet

agg

rega

tion

Ant

iinfl

amm

ator

y ef

fect

link

ed w

ith

plat

elet

agg

rega

tion

Syno

vial

flu

id

pros

tagl

andi

n E

MA

O I

nhib

itor

E

...M

odel

Pl

atel

et M

AO

B

inhi

bito

n

Pha

rmac

odyn

amic

P

aram

et.n

E

C..

30 m

cglm

L

EC ..

, 3

mcg

lmL

T

".:

2-6

min

EC

,., 0

.2 m

cglm

L

T".

: 2-6

min

No

corr

elat

ion

obse

rved

as

rec

omm

ende

d do

ses

too

high

E..

.: 1

00"..

1. E

.. ,2

3 ng

lmL

M

AO

. act

ivity

as

defi

ned

by p

lasm

a M

HPG

con

cent

ratio

n wa

s IO

OO

-fold

low

er

Ref

eren

c.s

Las

ka E

M, S

unsh

ine

A, M

arre

ro I

, Ols

en N

, Sie

gel C

, an

d M

c C

orm

ick

N. T

he c

orre

latio

n be

twee

n bl

ood

leve

ls o

f ibu

prof

en a

nd c

linic

al a

nalg

esic

res

pons

e.

Clin

Pha

rmac

ol T

her

1986

: 40:

I.

Cox

SR

, Yen

bder

Lug

t JT,

Gum

blet

on T

J, S

mith

RB

. R

elat

ions

hips

bet

wee

n th

rom

boxa

ne p

rodu

ctio

n,

plat

elet

agg

rega

bilit

y, a

nd s

erum

con

cent

ratio

ns o

f ib

upro

fen

and

flurb

ipro

fen.

Clin

Pha

nnac

ol T

her

1987

: 41

:510

. C

ox S

R, Y

enbd

erL

ugt J

T, G

umbl

eton

TJ,

Sm

ith R

B.

Rel

atio

nshi

ps b

etw

een

thro

mbo

xane

pro

duct

ion,

pl

atel

et a

ggre

gabi

lity,

and

ser

um c

once

ntra

tions

of

ibup

rofe

n an

d fl

urbi

prof

en. C

lin P

hann

acol

The

r 19

87:

41:

510.

Dro

mgo

ole

SH, F

irst

DE

, Des

iraj

u R

K,

Nay

ak R

K,

Jirs

henb

aum

MA

, and

Pau

lus

HE.

Tol

men

tin k

inet

ics

and

syno

vial

pro

stag

land

in E

,leve

ls in

rhe

umat

oid

arth

ritis

. Clin

Pha

nnac

ol T

hCr

1982

: 32:

371

.

Pres

sor

Res

pons

e to

Tyr

amin

e A

fter

24-

Hou

r A

pplic

atio

n O

f A S

eleg

iline

Tra

nsde

rmal

Sys

tem

In

Hea

lthy

Mal

es. 1

.S. B

arre

tt, T

. Hoc

hade

l, S.

Roh

atag

i, K

.E.

DeW

itt, S

.K. W

atso

n, J

. D

amow

, A.J.

Azz

aro

and

A.R

. D

iSan

to. J

. Clin

Pha

nnac

ol.,

37: 2

38-2

47,

1997

.

~

CI'I >

"1:1 ~ 2!

t:I ><

>

Dru

g/C

lass

/Ind

icat

ion'

D

osin

g P

harm

acok

inct

ic

PO-M

odO

i' P

D-M

arke

? Ph

arm

acod

ynam

ic

Rer

eren

ces

"1:1

"1:1

R~men'

Para

met

ers'

,J,l

Par

amet

ers

l'"l

Ant

ibio

tic.

Z

A

mpi

cilli

n S

OO

mgp

oQ6

F: 5

0%

Mod

ified

E...

Mod

el

E. C

oli b

acre

rial

AN

... :

·3.6

IogC

FU/m

L

Whi

te C

A, T

ooth

aker

RD

, Sm

ith A

L, S

latte

ry JT

. In

=

-h

F.:

15·2

5%

N ..

. ·M

ax n

umbe

r of

surv

ival

dilu

tion

AN

,. 1.

9 vi

tro e

valu

atio

n of

the

dete

rmin

ants

of t

he b

acre

ricid

al

>< T

, ,,:

1·1.

8 h

bacr

eria

with

out d

ilutio

n fa

ctor

B

AU

C:

1061

01

activ

ity o

fam

pici

llin

dosi

ng re

gim

ens

agai

nst

N,=

Mea

sure

d nu

mbe

r of

CFU

*hlm

L

Esc

heric

hia

Col

i. A

ntim

icro

b A

gent

s C

hern

othe

r ba

crer

ia

CFU

: Col

ony

fonn

ing

1989

: 33:

104

6.

A=C

hang

e un

it K

... li

min

atio

n m

te

cons

tant

B

AU

C=R

atio

of a

rea

unde

r the

bac

reria

l co

ncen

tratio

n tim

e cu

rve

and

the

initi

al

inoc

ulum

siz

e

N'=

N

.N

, ,

(N _

_ ;,

') ..

. -A

"+N

.

Rifa

mpi

cin

600

mg

per d

ay

F.: 6

0·90

",1,

Sigm

oida

l E

... M

odel

S.

aur

eus

bacr

eria

l E

... 6

6·7S

mg/

mL

H

ooge

rterp

JJ,

Mat

tie H

, Kru

l A

M, v

an F

urth

R. T

he

V,:

0.97

±0.

36I.

/kg

surv

ival

dilu

tion

effi

cacy

of r

ifam

pici

n ag

ains

t Sta

phyl

ococ

cus

aure

us in

C

L: 3

.5 ±

1.6

mL

lmin

lkg

fact

or

vitro

and

in a

n ex

perim

enta

l in

fect

ion

in n

orm

al a

nd

T, ,,

: 3.

5 ±

0.8

h gI

llDlu

ocyt

open

ic m

ice.

Sta

nd J

Inf

ect D

is 1

998:

20:

64

9.

Gen

tam

icin

1·

2.5

mgl

kg

F ,M: 1

00%

Si

gmoi

dal E

... M

odel

K.

pne

umon

ia"

E.g:

4.8

7 ±

0.1

5 L

egge

tt JE

, Fnt

in B

, Ebe

rt S,

Tot

suka

K, V

ogel

man

B,

per d

ose

iv/im

q

F.: <

10%

ba

crer

ial s

urvi

val

EC ..

. 2.3

4 to

.26

mgl

kg

Cal

ame

W, M

attie

H, C

raig

WA

. C

ompa

mtiv

e 8h

V

,: 0.

31 ±

0.1

0 I./

kg

dilu

tion

fact

or

antib

iotic

s do

sc-«

:lTec

t rel

atio

ns a

t sev

eral

dos

ing

CL:

0.8

2*C

rcat

inin

e in

terv

als

in m

urin

e pn

eum

oniti

s an

d th

igh

infe

ctio

n cl

eara

nce

+ 0

.11

mod

els.

J In

fect

Dis

198

9: I

S: 2

81.

mU

min

lkg

T, ,,

: 2·

3 h

Cel

\azi

dim

e 50

0-20

00 m

g F ,

M:91

%

Sigm

oida

l E

... M

odel

K.

pne

umon

iae

E.g:

4.6

9 ±

0.3

0 L

egge

tt JE

, Fnt

in B

, Ebe

rt S,

Tot

suka

K, V

ogel

man

B,

iv/i

mq

8 F.

: 21

±6%

ba

crer

ial s

urvi

val

EC ..

, 61.

4 ±

8.8

mgl

kg

Cal

ame

W, M

attie

H, C

raig

WA

. C

ompa

rativ

e V

,: 0.

23 ±

0.0

2 I./

kg

dilu

tion

fact

or

antib

iotic

s do

sc-«

:lTec

t rel

atio

ns a

t sev

eral

dos

ing

CL:

-C

reat

inin

e cl

ealll

Dce

in

terv

als

in r

oorin

e pn

eum

oniti

s an

d th

igh

infe

ctio

n m

Um

inlk

g m

odel

s. J

Infe

ct D

is 1

989:

IS

: 281

.

Til,

: 1.

6±0.

lh

Net

ilmic

in

\.S·2

mgl

kg p

er

Sigm

oida

l E

... M

odel

K.

pne

umon

iae

E...

: 4.8

7 ±O

.IS

Leg

gett

JE, F

ntin

B, E

bert

S, T

otsu

ka K

, Vog

elm

an B

, do

se m

g iv

/im q

T

, ,,:

2·3

h bl

crer

ial s

urvi

val

EC ..

, 2.3

4 to

.26

mgI

kg

Cal

ame

W, M

attie

H, C

mig

WA

. C

ompa

rativ

e 8

dilu

tion

fact

or

anllb

iotic

s do

se-«

:lTec

t rel

atio

ns a

t sev

ellli

dos

ing

inte

rval

s in

mur

ine

pneu

mon

itis

and

thig

h in

fect

ion

mod

els.

J In

fect

Dis

198

9: I

S: 2

81.

VI

\.0 -..J

~

QO

Dru

g/C

I.ss1

lndl

cado

nl

Dos

ing

Ph.

rm.c

okln

etlc

PO

oMod

eJ>

POoM

.rlc

e?

Ph.

rm.e

odyn

.m1c

R

efer

enc .

. R

glm

en'

P.r

. met

ers'

'''''

Para

met

ers

Bis

ehoa

ehon

ates

Pa

mid

rona

le (o

steo

poro

sis)

15

mgl

day

IV

V.:

29.5

L

E,..

Mod

el

Urin

ary

Cre

mer

s S,

et a

l. A

PK

and

PO

mod

el f

or in

inlv

enou

s in

fusi

on

CL:

181

± 7

8 m

Um

in

hydr

oxyp

rolin

e bi

spho

spho

nate

(pam

idro

nate

) in

ost

eopo

rosi

s. Eu

r J

Clin

Pha

rmac

ol 2

002;

57:8

83·8

90.

AC

E In

hibi

tors

C

ilaza

pril

2.5

rngp

oQO

F:

77.

5%

Sigm

oid

E...

Mod

el

Inhi

bitio

n of

plas

ma

E,.-E~

Bel

z G

O, K

irch

W, K

1ein

bloe

sem

CH

. A

ngio

tens

in-

(Cila

zcpr

ilat)

V.:

25.4

L

angi

oten

sin-

conv

ertin

g en

zym

e in

hibi

tors

: rel

atio

nshi

p be

twee

n C

L: 1

4.28

Uh

conv

ertin

g en

zym

e ph

arm

acod

ynam

ics

and

phar

mac

okin

etic

s. C

lin

(AC

E) a

ctiv

ity

Phar

mac

okin

etic

s 19

88:

IS: 2

95.

Cap

topr

il 12

.S-IS

O m

g po

F:

60-

75%

Si

gmoi

d E

... M

odel

In

hibi

tion

of pl

asm

a E,.-~

Bel

z G

O, K

irch

W, K

1ein

bloc

sem

CH

. A

ngio

tens

in-

TID

F.

: 25-

30%

an

giot

ensi

n-co

nver

ting

enzy

me

inhi

bito

rs: r

elat

ions

hip

betw

een

V.:

0.7

Ukg

co

nver

ting

enzy

me

phar

mac

odyn

amic

s an

d ph

arm

acok

inet

ics.

Clin

T'

I2:

1.9

h (A

CE)

act

ivity

Ph

arm

acok

inet

ics

1988

: IS

: 29

5.

Lis

inop

ril

10-4

0mgp

o F:

2S±

10"A

. Si

gmoi

d e..

.. Mod

el

Inhi

bitio

n o

f pla

sma

E ....

E~

Bel

z G

O, K

irch

W, K

lein

bloe

sem

CH

. A

ngio

tens

in-

QO

F.

: 0%

an

giot

ensi

n-co

nver

ting

enzy

me

inhi

bito

rs: r

elat

ions

hip

belw

een

V.:

2.4±

1.1.

4 U

kg

conv

ertin

g en

zym

e ph

arm

acod

ynam

ics

and

phar

mac

okin

etic

s. C

lin

CL:

4.2

±2.2

mU

min

/kg

(AC

E) a

ctiv

ity

Phar

mac

okin

etic

s 19

88:

IS: 2

95.

T'I2

: 12

h

Enal

april

10

-40

mg

or

F:41

±15%

Si

gmoi

d Eo

... M

odel

In

hibi

tion

of pl

asm

a .E

....

E~

Bel

z G

O, K

irch

W, K

1ein

bloe

sem

CH

. A

ngio

tens

in-

divi

ded

dose

F.

: 50-

60%

an

giot

ensi

n-co

nver

ting

enzy

me

inhi

bito

rs: r

elat

ions

hip

betw

een

V.:

1.7±

O.7

Ukg

co

nver

ting

enzy

me

phar

mac

odyn

amic

s an

d ph

arm

acok

inet

ics.

Clin

C

L: 4

.9±I

.S m

Um

inlk

g (A

CE)

act

ivity

Ph

arm

acok

inet

ics

1988

: 15

: 29S

. T

,12: I

I h

Perin

dopr

il 4-

16m

gpoQ

O

F: 6

S-9S

%

Sigm

oid

E....

Mod

el

Inhi

bitio

n of

plas

ma

Bel

z G

O, K

irch

W, K

lein

bloe

sem

CH

. A

ngio

tens

in-

(Per

indo

prila

l) F.

: 60%

an

giot

enSi

n-co

nver

ting

enzy

me

inhi

bito

rs: r

elat

ions

hip

betw

een

CL

:9.3

6 U

h co

nver

ting

enzy

me

phar

mac

odyn

amic

s an

d ph

arm

acok

inet

ics.

Clin

T'

I2: 2

S-30

h (A

CE)

act

ivity

Ph

arm

acok

inet

ics

1988

: IS

: 29S

.

Ram

ipril

2.

5-20

mgp

o F:

SO

-6O

%

Sigm

oid

E...

Mod

el

Inhi

bitio

n of

plas

ma

E ....

~

Bel

z G

O, K

irch

W, K

lein

bloc

sem

CH

. A

ngio

tens

in-

(Ram

ipril

at)

QO

F.

: 56%

an

giot

ensi

n.

conv

ertin

g en

zym

e in

hibi

tors

: rel

atio

nshi

p be

twee

n C

L:6

Uh

conv

ertin

g en

zym

e ph

arm

acod

ynam

ics

and

phar

mac

okin

etic

s. C

lin

T,12

: 2.4

±O.6

h

(AC

E) a

ctiv

ity

Phar

mac

okin

etic

, 198

8: I

S: 2

95.

AnB

lote

nsln

II

Reo

eeto

r A

ntaB

!DIs

ts

Losa

rtan

2S-I

OO

mgp

o F:

3S.

8 ±

IS.S

%

E..

Lin

k M

odel

Sy

stol

ic b

lood

E

...: 2

7.2

mm

Hg

Csa

jka

C, B

uclin

, T, F

attin

ger K

. Bru

nner

HR

, Bio

llaz

QO

Fb

: 98.

7%

pres

sure

(SB

P)

E ... 2

28 m

cglL

J.

Popu

latio

n Ph

arm

acok

inet

ic-P

harm

acod

ynam

ic

Vd:

0.4

5 ±

0.2

4 U

kg

K.,=

S.9h

· ' M

odel

ling

of A

ngio

tens

in R

ccep

tor B

lock

ade

in

CL:

8.1

± 1

.8 m

llmin

lkg

E...

: 23.

3 m

mH

g H

ealth

y V

olun

teer

s. C

lin P

harm

acok

in 2

002:

41

(2):

>

Tlf

2: 2

.5 ±

I h

D

iast

olic

blo

od

E ... I

S9m

cglL

13

7-15

2.

"CI

pres

sure

(OB

P)

K.,=

6.1

h"

"CI

l!I!J

2!

0 S<

Dru

glC

lass

l1nd

icat

ion'

D

osin

g Ph

orm

aeok

inet

lc

PD-M

odel

' P

D-M

arke

r' R

egim

en'

Plr

amet

ers"

'"

Can

desa

rtan

Irbe

sarta

n

Kle

rval

Abc

ixim

ab (

angi

opla

sty)

4-32

RIg

po

QD

F:

42%

E

.. L

ink

Mod

el

Syst

olic

blo

od

150-

300

RIg

po

QD

Ora

l and

in

trave

nous

ad

min

istra

tion

5-12

0 m

c&lk

g

O.2S

m&f

kg iv

bo

lus:

0.1

25

mc&

lkgl

min

for

12

h

Fb:

99.8

%

pteS

Sure

(SB

P)

Vd:

0.1

3 11

kg

CL:

0.3

7 m

Vm

inlk

g T

lI2: 9

.7 h

F: 6

0-80

%

F.: 9

0%

Vd:

0.7

2 t

0.20

11k

g C

L: 2

.12

to.5

4 m

Vm

inlk

g T1

/2: 1

3 t

6.2

h

V.:

23.0

-25.

9 L

C

L: 1

1.2-

15.5

lJh

T,

n: \

.2-2

.1

h

CL:

183

+/-

72 m

Vm

in

T,n

:0.5

h

E..

Un

kM

od

el

Dia

stol

ic b

lood

pr

essu

re (D

BP)

Syst

olic

blo

od

pres

sure

(SB

P)

Dia

stol

ic b

lood

pr

essu

re (D

BP)

GP

llb

lIlI

. an

t.p

nls

t E

..-M

odel

In

hibi

tion

of pl

atel

et

aggr

egat

ion

E..-

Mod

el

Rec

epto

r occ

upan

cy

% in

hibi

tion

of

plat

elet

agg

rega

tion

5-m

icro

moV

L ad

enos

ine

diph

osph

ate

(AD

P)

Phar

mae

odyn

amlc

Pa

.. m

eten

E

..:

30.2

mm

Hg

E ..

, 122

mcg

IL

K.,=

O.4

h·'

E,,;

.: 25

.1 m

mH

g E

,.,8

mcg

IL

K..=

O.3

h"

E..:

28.

7mm

Hg

E,.,

124

mcg

IL

K.,=

O.8

h·'

E..

: 26

.8 m

mH

g E

.. ,8

9mc fL

K

..=O

.8h·

E..

:10

0%

E

,., 5

8 ng

lmL

E,.,

72.

8± 6

.4 n

g/m

L

E ..

, 68.

9 t

9.2

ng/m

L

% in

hibi

tion

of

E .. , 1

41 t

16.

8 ng

/mL

pl

atel

et a

ggre

gatio

n 20

-mic

rom

oVL

AD

P

Ref

eren

ces

Csa

jka

C, B

uclin

, T, F

Illin

ger K

, Bru

nner

HR

, Bio

llaz

J. Po

pula

tion

Phar

mac

okin

etic

-Pha

rmac

odyn

amic

M

odel

ling

of A

ngio

tens

in R

ecep

tor B

lock

ade

in

Hea

lthy

Vol

unte

ers.

Clin

Pha

rmac

okin

200

2: 4

1 (2

): 13

7-15

2.

Csa

jb C

, Buc

lin, T

, Fat

tinge

r K, B

runn

er H

R, B

iolla

z J.

Popu

latio

n Ph

arm

acok

inet

ic-P

harm

acod

ynam

ic

Mod

ellin

g of

Ang

iote

nsin

Rec

epto

r Blo

ckad

e in

H

ealth

y V

olun

teer

s. C

lin P

harm

acok

in 2

002:

41

(2):

137-

IS2.

Phar

mac

okin

etic

s, P

harm

acod

ynam

ics

and

Safe

ty o

f a

Plat

elet

GPI

IblIl

Ia A

ntag

onis

t, R

GD

891,

Fol

low

ing

Intra

veno

us A

dmin

istra

tion

in H

ealth

y M

ale

Vol

unte

ers.

P.N

. Zan

niko

s, S.

Roh

atag

i, B

.K. J

ense

n,

S. D

ePhi

llips

, D. M

assi

gnon

, F. C

alic

, Mic

hel S

ibill

e an

d St

epha

ne K

irkes

seli.

J. C

lin P

harm

acol

., 40

: 12

45-

1256

,200

0.

Phar

mac

okin

etic

s an

d C

once

ntra

tion-

Eff

ect A

naly

sis

of I

ntra

veno

us R

GD

891,

A P

late

let G

Pllb

lllla

A

ntag

onis

t, U

sing

Mix

ed E

ffec

ts M

odel

ing

(NO

NM

EM

). P

.N. Z

anni

kos,

S. R

ohat

agi,

B.K

. Je

nsen

, S. D

ePhi

llips

, and

G. R

. Rho

des.

J. C

lin

Phar

mac

ol.,4

O:

1129

-114

0,20

00.

Abe

rnet

hy D

R, P

ezzu

llo J

, Mas

celli

MA

, Fre

deric

k B

, K

leim

an N

S, F

reed

man

J.

Phar

maC

odyn

amic

s o

f abc

ixim

ab d

urin

g an

giop

last

y:

com

paris

on to

hea

lthy

subj

ects

. C

lin P

harm

acol

The

r. 20

02 M

ar;7

1(3

): 18

6-95

.

> ~ ~ ~

Dru

giC

lasl

llnd

icat

lon'

---D

osin

g P

harm

amld

netl

e PD

-Mod

el'

PD

-Mar

ker'

Rea

lmen

' P

aram

eten

'''''

Ver

apam

il (d

+.I-

) (a

ntia

ngin

a.

anti a

rrhy

thm

ia.

antih

yper

tens

ive)

Nis

oldi

pine

.

Lans

opra

zole

Om

epra

zole

S-I

Om

giv

80-\

20 m

g Q

8h

20-6

0 m

g po

qd

IS-3

0 m

g po

qd

20-4

0 m

&'d

ay

qd

F: 2

2±8%

F.

: 90±

2% (d

+ 2.

S-fo

ld

high

er F

than

1-)

V.:

5.00

.1 U

kg

CL:

I S±

6 m

Um

inlk

g (d

+ is

O.S

-fold

low

er th

an 1

-) T'

I2: 4

.0±\

.S h

F:5

%

T'I2

:7-1

2 h

F:8

1%

F.: 9

7%

V.:

0.35

iO.O

S U

kg

CL:

6.2

3± 1

.6 m

Um

inlk

g T'

I2: 0

.9±

0.44

h

F: S

3±29

%

F.: 9

5%

V.:

0.34

iO.0

9 U

kg

CL:

7.5

± 2.

7 m

Um

inlk

g T

'I2:0

.7±

0.S

h

Cal

dum

Cha

nnel

Blo

cker

E

...-M

odel

E..-

Mod

el

PR-I

nter

val

prol

onga

tion

Supi

ne S

ysto

lic

Blo

od P

ress

ure

(SB

P) c

hang

e fro

m

base

line

Supi

ne D

iast

olic

B

lood

Pre

ssur

e (O

BP)

cha

nge

from

ba

selin

e P

roto

n P

amp

Inbl

blto

n M

odifi

ed E

... M

odel

H

IK A

TPas

e K

: app

aren

t rea

ctio

n ra

te c

onst

ant

k: a

ppar

ent t

urno

ver

rate

con

stan

t kI

K x

fjI:

appa

rent

di

ssoc

iatio

n co

nsta

nt

corr

ecte

d fo

r pla

sma

free

frac

tion

(fjI)

tll

2: h

alf-

life

of ef

fect

Mod

ified

E..

Mod

el

HIK

ATP

ase

K: a

ppar

ent r

eact

ion

rate

con

stan

t k:

app

aren

t tum

over

ra

te c

onst

ant

klK

x fjI

: app

aren

t di

ssoc

iatio

n co

nsta

nt

corr

ecte

d fo

r pla

sma

free

frac

tion

(fjI)

tll

2: h

alf-

life

of e

ffec

t

Phar

mae

odyn

amle

P

aram

eten

E,.O

l"'E

,o (d

YII

E

,.,po

(d.Il

"'12O

O0

nglm

L

E.o.

iv (d

.I)0-

4OO

S nw

mL

E...

:27.

9%

E,o

,0.9

9-2.

62 m

cWm

L

E...

:36.

4%

E,o

,0.9

9-2.

62 n

wm

L

K :

0.33

9 ±

0.0

02 m

MIh

k

: 0.0

537

± 0.

0006

h"

klK

xfjl

: I

nM

tll2

eff

ect:

12.9

h

K:

I.3H

O.1

7mM

1h

k: 0

.025

2 ±

0.0

019

h"

klK

xfj

l:ln

M

tll2

eff

ect:

27.S

h

Ref

eren

ees

Echi

zen

H. V

ogel

gesa

ng B

. Eic

helb

aum

M.

Eff

ects

of

d.l-v

erap

amil

on a

rtrio

vent

ricul

ar c

ondu

ctio

n in

re

latio

n to

its

ster

oese

lect

ive

first

-pas

s m

etab

olis

m.

Clin

Pha

rmac

ol T

her

1985

: 38

: 71.

Scha

efer

HG

. Hei

nig

R, A

hr G

. Ade

lman

n H

. Tet

zlof

f W

. Kuh

lman

n J.

Phar

rnac

okin

etic

-pha

rrna

cody

nam

ic

mod

ellin

g as

a to

Ql t

o ev

alua

te th

e cl

inic

al re

leva

nce

of

a dr

ug-f

ood

inte

ract

ion

for a

nis

oldi

pine

con

trolle

d­re

leas

e do

sage

form

. Eu

r J C

lin P

harm

acol

. 19

97;5

1(6)

:473

-80

Kat

ashi

ma

M. Y

amam

oto

K. T

okum

a Y

. Hat

a T.

Sa

wad

a Y

.1ga

T.

Com

para

tive

phar

mac

okin

etic

l ph

arm

acod

ynam

ic a

naly

sis

of pr

oton

pum

p in

hibi

tors

om

epra

zole

. Ian

sopr

azol

e an

d pa

ntop

razo

le. i

n hu

man

s. E

ur J

Dru

g M

etab

Pha

rrna

coki

net.

1998

Jan

­M

ar;2

3(1)

:19-

26.

Kat

ashi

ma

M. Y

amam

oto

K. T

okum

a Y

. Hat

a T.

Sa

wad

a Y

.1ga

T.

Com

para

iive

phar

mac

okin

etic

l ph

arm

acod

ynam

ic a

naly

sis

of pr

oton

pum

p in

hibi

tors

om

epra

zole

. lan

sopr

azol

e an

d pa

ntop

razo

le. i

n hu

man

s. E

ur J

Dru

g M

etab

Pha

rrna

coki

net.

1998

Jan

­M

ar;2

3(1)

:19-

26.

~ >­ "0 ;g 2: ~

Dru

giC

lass

/lnd

leat

lon'

D

osln

l P

hlrm

aeok

lnet

le

-p

D-M

od

er-

-p

j):M

ark

er'

Panl

opra

zole

Nob

eras

tine

Feno

tero

l

Alb

uter

ol

Rea

imen

l P

aram

eten

l ,1,

J

4Om

gpoq

d F

:77%

10 m

g po

IV b

olus

, in

fusi

on, n

asal

2-4

mgl

dose

O

ral 3

-4

times

/day

up

to

32 m

glda

y; 1

·2

inha

latio

ns

ever

y 4-

6 h

up

to 1

2 in

hala

tions

/day

or

ora

l su

blin

gual

F,:9

8%

v.: 1

1·24

L

CL:

7.5

± 2.

7 m

Um

inlk

g T

'Il:

I h

VjF

:192

8±32

L

T'Il

: IS

h

V.:

14

0±

70

L

CL:

63

± 2

4 LI

b T

,":

3.3

± 1

.2 h

V.:

156±

38L

C

L: 2

9± 7

LIb

T

,":

3.9

± 0.

8 h

Mod

ified

E..

Mod

el

K: a

ppar

enl r

eaet

ion

rale

con

stan

t k:

app

aren

t tur

nove

r ra

te c

onst

ant

kIK

x fp

: ap

pare

nt

diss

ocia

tion

cons

tant

co

m:c

ted

for p

lasm

a fre

e fr

actio

n (f

p)

tll2

: hal

f-lif

e o

f eff

ect

HlK

AT

Pase

Ant

lbls

tam

ln ..

: H,B

1ock

en

SiJll

llOid

E..

Lin

k Pl

aceb

o co

rrect

ed

Mod

el

hist

amin

e in

duce

d w

heal

inhi

bitio

n

Plac

ebo

corr

ecte

d hi

stam

ine

indu

ced

nan:

inhi

bitio

n

Bet

arA

dren

ergi

c A

lOnl

sts:

Bro

aebl

odll

aton

Si

JllllO

id E

... L

ink

Airw

ay re

sist

ance

M

odel

(R

AW

)

SiJll

llOid

E...

Mod

el

Hea

rt ra

te (H

R)

Forc

ed e

xpira

tory

vo

lum

e in

I s

ec

(FE

VI)

Hea

rt ra

te (H

R)

Pha

rmae

odya

amle

P

aram

eten

K

: O

.I34±

o.o0

6mM

1h

k : 0

.1>15

1 ±

0.00

02 h

·' kI

K x

fp:

2.3

nM

tl/2

eff

ect:

45.9

h

E..:

9O%

E

,., 1

.2:1

:0.2

ngl

mL

N

: 1.

0±.0

.2

Keo

=O.3

9±O

.13

h·'

E...:

9O%

E

,o,0

.3:l(

).\ n

glm

L

N:0

.8±.

0.2

Keo

-O.0

9±O

.03

h·'

E,.,

0.38

ngl

mL

N

:I

Keo

=12h

·'

E,.,

\.I

ngl

mL

N

:I

1<,,:

12 h

·'

E,.,

S n

glm

L N

:2

EIO,

18

nglm

L N

:I

Ref

eren

e ..

Kat

ashi

ma

M, Y

amam

oto

K, T

okum

a Y

, Hat

a T,

Sa

wad

a Y

, 19a

T.

Com

para

tive

phar

mac

okin

etie

l ph

arm

acod

ynam

ic a

naly

sis

of pr

oton

pum

p in

hibi

tors

om

epra

zole

, lan

sopr

azol

e an

d pa

ntop

razo

le, i

n hu

man

s. E

ur J

Dru

g M

etab

Pha

rmac

okin

et. 1

998

Jan·

M

ar,2

3(1)

: 19-

26.

Hey

kant

s et

al.

The

in v

ivo

stud

y of

drug

act

ion.

Van

D

oxte

l CJ,

Hol

ford

NH

G, D

anho

f, cd

s. El

sevi

er:

1992

: 33

5.

Hoc

hhau

s G

, Sch

mid

t EW

, Rom

inge

r KL,

Mol

lman

n H

. Phl

rmac

okin

etie

ldyn

amic

cor

rela

tion

of p

ulm

onar

y an

d ea

rdia

c ef

fect

s of

feno

tero

l in

asth

mat

ic p

atie

nts

afte

r diff

eren

t rou

tes

of a

dmin

istra

tion.

Pha

rm R

es

1992

: 9: 2

91.

Hoc

hhau

s G

, Mol

lman

H. P

KlP

D a

naly

sis

of a

lbut

erol

ac

tion:

app

licat

ion

to a

com

para

tive

asse

ssm

ent o

f ~

adre

nerg

ic d

rugs

. Eur

J P

harm

Sci

199

3: I

.

> ~ Z =

5< ~ -

Dru

g/C

lass

/Ind

icat

ion'

D

oiln

g Ph

.,.m

acok

lnet

ic

PD-M

odeJ

' P

D-M

arkU

' R

egim

en'

Par

amet

en',u

T

erbu

talin

e 0.

25 m

g/do

se

Vd:

79

± 2

7L

Sigm

oid

E..

Unk

A

irway

resi

stan

ce

Subc

utan

eous

C

L: 2

2 ±

6.7

lJh

M

odel

(R

AW

) re

peat

ed o

nce

at

TlI2

: 2.5

± 0

.5 h

15

-30

min

utes

or

sub

cuta

neou

s or

2.5

-10

mew

'min

In

fusi

on

effe

ctiv

e m

axim

um d

ose

17.5

-30

mew

'min

E...

Mod

el

Forc

ed e

xpira

tory

vo

lum

e in

I s

ec

(FE

VI)

Hea

rt ra

te (

HR

)

Cor

tIco

ster

oIds

(aD

ti-iD

Dam

mal

ory/

asth

ma)

Phar

mac

odyn

amic

P

aram

eten

El

O, 3

.7 n

w'm

L N

:I

Kco

-7.S

h"

E,.,

2.3

nw

'mL

N:I

K

co-5

.5 h

"

ElO,

II

nw'm

L

*RR

A=

rela

tive

gluc

ocor

ticoi

d re

cept

or a

ffin

ity [d

exam

etha

sone

-IO

OI

Pred

niso

ne

Met

hylp

redn

isol

one

17-B

eclo

met

haso

ne

mon

opro

pion

ate

(adm

inis

tere

d as

B

eclo

met

haso

ne

dipr

opri

onat

e)

Bud

elon

ide

5-60

mgp

o da

ily i

n I

10 4

di

vide

d do

ses

2-60

mgp

o da

ily in

110

4 di

vide

d do

ses

168-

S40

meg

in

hale

d in

one

or

two

div

ided

do

ses

200-

600

meg

in

hale

d in

one

or

two

divi

ded

dose

s

F:SO

%

F(in

hale

d): N

/A

F.: 7

5%

Vd:

70L

C

L: 1

5lJh

T

",:

3.2h

F:99

%

F(in

hale

d):

F.:

77%

V

d: S

OL

CL:

21l

Jh

T'I2

:2.6

h

F:2

6%

F(in

hale

d): 3

6%

F.:

Vd:

424L

C

L: 1

20 l

Jh

T'I2

: 6.5

h

F: 1

\%

F(in

hale

d): 2

S%

F.:S

8%

Vd:

IS3

-217

.5L

C

L: 8

0-84

lJh

T

'I2:2

.8h

Indi

rect

Res

pons

e M

odel

Indi

rect

Res

pons

e M

odel

Indi

rect

Res

pons

e M

odel

Indi

rect

Res

pons

e M

odel

Lym

phoc

yte

Supp

ress

ion

(LS)

G

ranu

locy

te

Indu

ctio

n (G

I)

Cor

tisol

Sup

pres

sion

(C

S)

Lym

phoc

yte

Supp

ress

ion

(LS)

G

ranu

locy

te

Indu

ctio

n (G

I)

Cor

tisol

Sup

pres

sion

(C

S)

Lym

phoc

yte

Supp

ress

ion

(LS)

G

ranu

locy

te

Indu

ctio

n (G

I)

Cor

tisol

Sup

pres

sion

(C

S)

Lym

phoc

yte

Supp

ress

ion

(LS)

G

ranu

locy

te

Indu

ctio

n (G

I)

Cor

tisol

Sup

pres

sion

(C

S)

E ...

.. : I 8

.6 ±

8.0

ng/

mL

E5

OG':

16.7

± 6

.8 n

w'm

L E.

..LS.

cs: 1

00%

E.

..G':

0.68

±0.

12%

K

.,.:

0.35

± 0

.07

h"

RR

A":

16

E,..

..:4.

8 ±

2.7

nw

'mL

E50G

,: 3.6

± 2

.0 n

w'm

L E.

..LS.

cs: 1

00%

E.

..G':

0.68

±0.

12%

K

.,.: 0

.35

± 0

.07

h"

RR

A":

42

RR

A":

134

5

RR

A":

935

Ref

eren

ces

Oos

terh

uis

B, B

raat

P, R

oos

VM

, Wer

ner J

and

van

Box

tel C

J. Ph

arm

acok

inet

ic-p

harm

acod

ynam

ic

mod

elin

g of

terb

utal

ine

bron

chod

ilatio

n is

ast

hma.

Clin

Ph

arm

acal

Tho

r 19

86: 4

0: 4

69.

Mol

lman

n H

, Hoc

hhau

s G

, Roh

atag

i S, B

arth

J,

Der

cndo

rf H

. Pha

rmac

okin

etic

lpha

rmac

odyn

amic

ev

alua

tion

of de

Daz

acar

t in

com

paris

on 1

0 m

ethy

lpre

dnis

olon

e an

d pr

edni

solo

ne. P

harm

Res

. 19

95 J

ul;1

2(7)

:I096

-100

.

Mol

lman

n H

, Hoc

hhau

s G

, Roh

atag

i S, B

arth

J,

Der

cndo

rf H

. Pha

rmac

okin

etic

lpha

rmac

odyn

amic

ev

alua

tion

of de

flaza

cort

in c

ompa

rison

to

met

hylp

redn

isol

one

and

pred

niso

lone

. Pha

rm R

es.

1995

Jul

;12(

7):I0

96-1

00.

Roh

atag

i S. P

hD T

hesi

s. P

harm

acok

inct

ic a

nd

Phar

mac

odyn

amic

mod

ellin

g of

mC

!hyl

pred

niso

lone

an

d pr

edni

solo

ne a

fter s

ingl

e an

d m

ultip

le

adm

inis

tratio

n, 1

995.

Roh

atag

i S. P

hO'T

hesi

s. P

harm

acok

inet

ic a

nd

Phar

mac

odyn

amic

mod

ellin

g o

f mC

!hyl

pred

niso

lone

an

d pr

edni

solo

ne a

fter s

ingl

e an

d m

ultip

le

adm

inis

tratio

n, 1

995.

t >

~ ~ ~

>

"'1:1

Dru

g/O

assl

lndi

catio

n'

Dos

ing

Phar

mac

okin

etic

PD

-Mod

et'

PO-M

arke

r>

Phar

mac

odyn

amic

R

efer

ence

s "'1:

1 I.!

'l R

!JIlm

en'

Par

amet

ersl

,u

Par

amet

en

Z

Flun

isol

ide

500-

2000

meg

F:

7%

Indi

rect

Res

pons

e ly

mph

ocyt

e R

RA

": I

SO

Roh

alag

i S. P

hD T

hesi

s. Ph

arm

acok

inct

ic a

nd

1:1

inha

led

in o

ne

F(in

hale

d): 3

9"4

Mod

el

Supp

ress

ion

(LS)

Ph

arm

acod

ynam

ic m

odel

ling

of m

ethy

lpre

dnis

olon

e ><

or tw

o di

vide

d F.

: 80

%

Gra

nulo

cyte

an

d pr

edni

solo

ne a

fter s

ingl

e an

d m

ultip

le

dose

s V

d: 6

1-96

l In

duct

ion

(01)

ad

min

islJ

atio

n, 1

995.

C

l: 5

6·65

IJh

C

ortis

ol S

uppr

essi

on

Till:

1.

2-1.

9h

(CS)

Flut

icas

one

Prop

iona

te

88-6

60 m

eg

F: 1

%

Indi

rect

Res

pons

e ly

mph

ocyt

e E

......

.a:0

.34

±0.

16

Dyn

amic

Mod

elin

g of

Cor

tisol

Red

uctio

n A

fter

inha

led

in tw

o F(

inha

led)

: 26%

M

odel

Su

ppre

ssio

n (L

S)

ng/m

L In

hale

d A

dmin

istra

tion

of F

lutic

ason

e Pr

opio

nate

. S.

di

vide

d do

ses

F.: 9

0%

Gra

nulo

cyte

E

....c

s: 1

00%

R

ohal

agi,

A. B

ye, C

. Fal

coz,

A.E

. Mac

kie,

B.

Vd:

318

L In

duct

ion

(01)

R

RA

": 1

800

Mei

bohm

, H. M

Ollm

ann

and

H. D

eren

dorf

. 1. C

lin.

CL:

6S-

691J

h C

ortis

ol S

uppr

essi

on

Phar

mac

ol. 3

6: 9

38-9

41,

1996

. Ti

ll: 1

1.5

(CS)

Tna

mei

nolo

ne A

ceto

nide

40

0 -

2000

meg

F:

23%

In

dire

ct R

espo

nse

lym

phoc

yte

E ...

.. : 0

.24

± 0

.7 n

g/m

L Ph

arm

acok

inet

iclP

ham

eody

nam

ic E

valu

atio

n of

in

hale

d in

one

F(

inha

led)

: 22%

M

odel

Su

ppre

ssio

n (L

S)

E ...

. , : 0

.22

± 0

.06

ng/m

L Tr

iam

eino

lone

AC

elon

ide

Afte

r In

lJav

enou

s, O

ral a

nd

or tw

o di

vide

d F.

: 71%

G

ranu

locy

te

E,..

.: 0

.14

± O

.04n

g/m

L In

hale

d A

dmin

islJ

atio

n. S

. Roh

alag

i, O

. Hoc

hhau

s, H

. do

ses

V.:

103l

In

duct

ion

(GI)

E.

."LS:

55%

M

Ollm

ann,

J. B

arth

, H. S

ourg

ens,

M. E

rdm

ann

and

H.

Cl:

371

Jh

Cor

tisol

Sup

pres

sion

E

....c

s: 1

00%

D

eren

dorf

. J. C

lin. P

harm

acol

. 35:

118

7-11

93, 1

995.

Ti

ll: 2

.0h

(CS)

E.

."GI:

60±

7%

K...:

0.6

4 ±

0.1

3 h·

1

RR

A: 2

33-3

46

Bet

a-B

loek

en

Prop

rano

lol

10-3

0 m

gpo

Q

F:2

6±10

%

E...

.Mod

el

Exer

cise

Ind

uced

E

....:

83 ±

6 b

eats

/min

B

rynn

e L,

Paa

lzow

LK

, Kar

lsso

n M

O. M

echa

nism

-(a

ntia

rrhy

thm

ia)

6-Sh

F.

: 87

±6%

T

achy

card

ia

E,.:

18.

! ±

4.3

ng/

ml

base

d m

odel

ing

of re

boun

d la

chyc

ardi

a af

ter c

hron

ic I

-V

.: 4.

3 ±

0.6

Ukg

pr

opra

nolo

l inf

usio

n in

spo

ntan

eous

hyp

erte

nsiv

e ra

ts.

Cl:

16

± 5

mU

min

lkg

J Ph

arrn

acol

Exp

The

r. 19

99 A

ug;2

9O(2

):664

-71.

Ti

ll: 3

.9 ±

0.4

h

Line

ar M

odel

Ex

erci

se I

nduc

ed

S10J

IC"'2

S.9

± 2

.S

Tac

hyca

rdia

be

ats"

min

/(m

in· m

eg)

Met

opro

lol

100-

450

F: 3

8± 1

4%

E."

Mod

el

Exer

cise

Ind

uced

E

,...:

103

± 6

bea

ts/m

in

Bry

nne

L, P

aalz

ow L

K, K

arls

son

MO

. Mec

hani

sm-

(ant

iarr

hyth

mia

) m

gida

y in

2-3

F.

: II

± 1

%

Tac

hyca

rdia

E

,.: 5

0.6

± 1

52 n

g/m

l ba

sed

mod

elin

g of

rebo

und

tach

ycar

dia

afte

r chr

onic

1-

divi

ded

dose

s V

.: 4.

2 ±

0.7

Ukg

pr

opra

nolo

l inf

usio

n in

spo

ntan

eous

hyp

erte

nsiv

e ra

ts.

CL:

15

± 3

mU

min

lkg

J Ph

arm

acol

Exp

The

r. 19

99 A

ug;2

9O(2

):664

-71.

Till:

3.2

± 0

.2 h

Li

near

Med

el

Exer

cise

Ind

uced

Sl

ope=

4.48

± 0

.39

Tac

hyca

rdia

be

ats·

min

/!m

in"

mes

l Im

mun

osul

!l!re

ssaD

ts

Cyc

losp

orin

(T

rans

plan

t) I 5

mgl

kg/d

ay

F:2

8± 1

8%

Fixe

d Ef

fect

N

ephr

otox

icity

N

ephr

otox

icity

>200

R

ohal

agi S

, Cal

ic F

, Har

ding

N,

Ozo

ux M

-L,

po

F.: 9

3 ±

2%

ng/m

L fo

r sle

ady-

slat

e K

irkes

scli

S, D

eLei

j L,

Jen

sen.

BK

Pha

rmac

okin

etic

s, V

.: 4.

5 U

kg

troug

h co

ncen

tratio

ns

Phar

mac

odyn

amic

s an

d Sa

fety

of I

nhal

ed C

yclo

spor

in

CL:

5.7

mU

min

lkg

A (A

DI6

28)

Afte

r Sin

gle

and

Rep

eate

d Ti

ll: 1

0.7h

Fi

xed

Effe

ct

Imm

unos

uppr

essi

on

Imm

unos

uppr

essi

on>

20

Adm

inis

lJat

ion

in H

ealth

y M

ale

and

Fem

ale

Subj

ects

o n

g/m

L fo

r ste

adY

-Sla

te

And

Ast

hmat

ic P

atie

nts.

J C

lin P

harm

acol

., 20

00:4

0:

troug

h co

ncen

lJat

ions

12

11-1

226.

U

I eo

Dru

g/C

I •• s

IInd

ic.d

on'

Dos

ing

Ph.

rm.c

okin

etic

-P

D-M

odef

-P

));.M

ariie

r' R

egIm

en'

P.r

amet

er.' .

....

Dau

noru

bici

n (a

cute

no

n lym

phoc

ytic

leuk

emia

, ly

mph

oma)

Dox

orub

icin

(br

east

ca

ncer

, ant

ineo

plas

tic

agen

t)

5-Fl

uoro

urac

il (tr

eatm

ent

of so

lid tu

mor

s su

ch a

s br

east

can

cer)

Cyt

arab

ine

(lym

phom

as

and

leuk

emia

s)

Cis

plat

in

30-6

0 m

g/m

' iv

fo

r 3-

5 da

ys,

repe

at d

ose

in

3-4

wee

ks

(pro

toco

l ba

sed)

60-7

5 ril

r/m' iv

si

ngle

, rep

eat

dose

eve

ry 2

1 da

ys (p

roto

col

base

d)

400-

500

mg/

m'/d

ay iv

fo

r 4-5

day

s

200

mg/

m'/d

ay

iv f

or 5

day

s at

2

wee

k in

terv

als

50-7

0 m

g/m

' iv

ever

y 3-

4 w

eeks

V.:

40 U

kg

T,n:

24-

48 h

F:5

%

F.: 7

6%

V.:

682

±433

Um

' C

L: 6

66±3

39 m

Um

ini ~

T,n

: 26±

17 h

F.: 9

4%

V.:

35±2

1 U

kg

CL:

9.6

±6.9

mU

min

lkg

T,n

: 53±

41 h

F:<2

0%

F.:

13%

V

.: 3.

0±1.

9 U

kg

CL:

13±

4 m

Um

inlk

g T

,n:

2.6±

0.6

h

V.:

0.28

tO.0

7 U

kg

CL:

6.3

±1.2

mU

min

lkg

T,n

: 0.5

3tO

.10

h

Fixe

d Ef

fect

Mod

el

Une

arM

odel

Une

arM

odel

E...

and

expo

nent

ial

Fixe

d-E

ffec

t /lo

gist

ic

regr

essi

on

Fixe

d Ef

fect

Onc

olO

&)'

Mye

lobl

ast:

eryt

hroc

yte

activ

ity

ratio

Sho

rt-te

rm tu

mor

re

spon

se

Nad

ir W

hite

blo

od

cells

(WB

C)

Freq

uenc

y o

f St

omat

itis

Rem

issi

on r

ate

Res

pons

e to

The

rapy

Gas

troin

test

inal

to

xici

ty

Ph.r

mac

odyn

amlc

P

aram

eten

Res

pond

ers

to C

OJl1

lIete

hc

mat

oloi

c re

spon

se

have

gre

ater

myl

eblo

st:

eryt

hroc

yte

activ

ity ra

tio

Plas

ma

AU

Cu

shor

t­te

rm tu

mor

resp

onse

(r

'-o.6

7)

Css

u N

adir

WB

C (

r'--

0.28

)

C.S

O (

"=-(

).85

)

Hig

her c

ompl

ete

rem

issi

on ra

te >

75

roM

co

ncen

tratio

n

AU

C>

SO

H 1

87

resp

onde

d to

ther

apy

AU

C >

451

had

gre

ater

ga

stro

inte

stin

al to

xici

ty

Ref

eren

ces

Gre

ene

W, H

ulTm

an D

, Wie

mik

PH

, Sch

miff

S,

Ben

jam

in R

, Bac

hur N

. H

igh-

clos

e da

unor

ubic

in

ther

apy

for a

cute

non

lym

phoc

ytic

leuk

emia

: co

rrel

atio

n of

resp

onse

and

toxi

city

with

ph

arm

acok

inet

ics

and

intra

cellu

lar d

auno

rubi

cin

redu

cllS

cact

ivity

. C

ance

r 19

72: 3

0: 1

419.

Rob

ert J

, Dlia

dis

A, H

aem

i B, C

ano

JP, D

uran

d M

and

Lan

grad

c C

. Ph

arm

acok

inet

ics

of ad

riam

ycin

in

patie

nts

with

pat

ient

s w

ith b

reas

t can

cer:

corr

elat

ion

betw

een

phar

amco

kine

tics

para

met

ers

and

shor

t-ter

m

clin

ical

resp

onse

. E

urjC

ance

rClin

Onc

ol

1982

: 18

-73

9.

Ack

land

SP,

Rat

ain

MJ,

Vog

elza

ng N

J, C

hoi K

E,

Rua

ne M

, Sin

kule

JA

. Ph

arm

acok

inet

ics

and

phan

naco

dyna

mic

s of

long

-term

cO

ntin

uous

-infu

sion

do

xoru

bici

n. C

lin P

hara

mco

l The

r 19

89: 4

0: 4

5.

Trum

p D

I., E

gorin

MJ,

Forr

est A

, Wils

on J

KV

, R

emic

k S,

Tut

sch

KD

. Pha

rmac

okin

etic

and

ph

arm

acod

ynam

ic a

naly

sis

of f1

uoro

cil d

urin

g 72

hou

r co

ntin

uous

infu

sion

with

and

with

out d

ipyr

idam

ole.

J

C1in

000

0119

91: 9

: 202

7.

Plun

keU

W, I

acob

oni S

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AAPS, 23 Absorbable dose, Dabs, 61 Absorption, 144, 177-178, 251 ACAT, 149,237 Accuracy/precision, 28 Acetaminophen, 80-81, 211, 531 Active metabolite, 13, 90 Acyl glucuronide, 39,40,42 ADME, 1,3,54,75 Ah,119 AIC, 355 Albuterol, 541 Alendronate, 427

biopharmaceutics, 452 clinical pharmacology, 439 dose proportionality, 461 drug-drug interactions, 466 human phannacokinetics, 451 mechanism of action, 431 preclinical pharmacokinetics, 437 preclinical phannacology, 434

Alfentanil, 531 Allometric scaling (see interspecies scaling), 99,

138 Alprazolam, 533 Alzheimer, I, 26+-265 Amikacin therapy, 490 Analytical qualifiers, 29 ANDA,209 Angiotensin, 13 Animal exposure, 7 Animal models, 9 APCI,22 API,22 Apolysichrons, 142 Aptamers, 10 Artificial organ systems, 10 Assay error, 375 Atorvastatin, 32, 77-78 Atracurium, 530 Autoinduction, 316

INDEX

BA,226 BAlBE, 3, 225 Basiliximab, 256 Bayes' theorem or Bayesian, 374, 481, 483 BCS, 196,198-199,228,230-231 BE,226 Benzodiazepines, 261 Beta-blockers, 543 Bile-duct cannulated, 87 Biliary clearance, 163 Bioanalytical methods, 21 Bioavailability, 197 Biological license application, 6 Biological matrix, 28 Biomarker, 3, 12, 14,338,351 Biotechnology, 8, 10 Biowaivers, 225, 234 Bisphosphonates, 436 BMD,429 Bootstrap, 40 I Boxenbaum approach, 160 Brain weight or BRW, 99, 143, 159 Bridging data package, 280 Bridging studies, 364 Bupropion, 36 Busulfan therapy, 493

14C mass effects, 36 Caco-2, 237,313 Caloric load, 203 Captopril, 538 CAR,119 Carbohydrate meals, 200 Carcinogenicity, 3 Carrier-mediated, 55, 200 Cassette dosing, 29, 87 CAT, 57-58,60,63 CDER,248 Cefprozil, 274 Celecoxib, 405

allometric scaling, 418

545

546

Celecoxib (continued) clinical dose prediction, 418 drug~gintemctions,408 food effects, 421 metabolism, 406 PM, EM,413 toxicokinetics, 409 2C9,408--409

21CFR,225 Chemical derivatization, 21 Child-Pugh, 293 Chromatographic, 22, 28 Chronothempeutic, 189 CI-I007, 104 CID,25 Ciprofloxacin, 289 Clearance, 75 Clinical development, 2, 7 Clinical trial simulation, 365 CLND,43,44 Clockwise hysteresis, 344 Clozapine, 45 CMC, 226, 228 cMOAT,206 Cocktail, 320 Co-elution, 36 Common technical document, 17 Compartment modeling, 53-54, 335 Corticosteroids, 349, 542 Cortisol, 359, 366 Covalent binding, 88, 91 COx, 405 Creatinine clearance, 378 CRF,8 CRIMS,45 Cryopreserved, 85 Cyclosporine, 252, 543 CVP, 77, 80, 307

induction, 311 inhibition, 308 2CI9,277 2C9,277 206,9, 82, 277 3A4,I80-181

Dso. 349 Data transformation, 353 Data warehousing, 8, 10 Dedrick plot, 142-143 Demographics, 246 Detection limit, 29 Dialysis, 286 Diazepam, 37,532 Diffusion coefficient, 59--60 Diffusion rate limited, 134 Digoxin thempy, 491 Direct injection, 24 Direct link, 341 Direct response, 341 Disopyramide. 215 Dispersion model, 62 Dissolution, 54-55, 60

Dissolution time, 61 Distribution, 151, 252 DMP-728,32 DMPK, 133 Dofetilide, 326 Dosagefonn, 55, 195,201 Dose. 201 Dose adjustment, 246, 288, 298 Dose individualization, 477 Dose proportionality, 3 Dose selection, 167 Doxacurium, 530 Doxorubicin, 544 DRso, 349 Drug development, I Drug-disease intemction, 364

INDEX

Drug~g intemction, 9, 75, 105,307,364 Drug

flux, 196 interaction, 3 intemctions, elderly, 264 metabolism, 75 metabolizing enzyme, 75-76 particle dissolution, 59 property, 196 solubility, 196, 198

Drug-food effects, 196 Drug-nutrient interaction, 195 Duodenum, 55-56, 181

e-ADME,71 ECso, 336 Effective permeability, 61 Efficacy bridging, 280 Efflux transporters, 57 Electrospray ionization (ESI), 22 Elimination, 252 Emax,340, 346-347 End of phase I meeting, 2 End of phase II meeting, 2 Endogenous ligand, 13 Enterion, 178, 182-184 Enzyme induction, 115 Enzyme inhibition, 107, III Epimers,32 Ethnicity, 246, 275 Everolimus, 295 Exposure, 337 Exposure-response, elderly, 263 Extended release, 188 Extensive metabolizers, 102 Extraction ratio, 155

F2,239 FaSSIF,237 Fat meals, 199 FDA, 23,54 FDA modernization Act or FDAMA, 5,248 Fentanyl, 531 FeSSIF,237 FEV .. 360 Fexofenadine, 320 Fick's law, 59

INDEX

First in human, 3, 363 First order kinetics, 55 First-pass metabolism, 55, 196,205 Fisher information, 376, 483 Fixed effect, 339 Fluid volume, 202 Flumazenil, 533 Fluvoxamine,270 FO,375 FOCE,374 Food effect, 363 Food effect BNBE, 209 Food-drug interaction, 195 Fosinopril, 25-27 Fosinoprilat, 25-27 Fraction absorbed, 57,146-148 Functional proteomics, 8

Gabapentin, 216 Ganciclovir, 61, 62 Gastric emptying, 55,196-197,203 Gastric pH, 55,214 Gastroplus™, 149-150 Gauss-Newton, 354 GC,21 GCIMS,22 Gender effect, 363 Gentamicin therapy, 487, 489,537 Geriatric labeling guidance, 266 Geriatric population, 246, 260 Gl residence time, 203 Gl tract, 145 GLP, 12,30,315 Gonadal steroids, 271 Goodness of fit, 354 Grapefruit juice, 327

Hard link, 343 Hepatic clearance, 86, 96, 98-99 Hepatic extraction ratio, 86, 98 Hepatic function, 293 Hepatic impairment, 291 Hepatic metabolism, 62 Hepatocytes, 35, 84-85 HepG2, 85, 119 HER2,9 Herceptin®,9 High frequency capsule, 182 HPLC,21 HPMC,215 HTS,8 Human drug absorption (HDA), 177 Human metabolic clearance prediction, 96 Human oral bioavailability, 53-54 Hysteresis loop, 357

Ibuprofen, 531, 536 ICso and 1(;, 109 Ileum, 55-56, 181 IMMC,203 Immediate release (lR), 53,225 Impurities, 31 In silico, 8, 53

IND,2,76 Indinavir, 213 Indirect link, 341 Indirect response, 342-343 Indomethacin, 41,535 Induction, 75, 77 Influx transporters, 57 Inhibition, 75, 77 Inhibition kinetics, 108 Initial estimates, 354 Innovation, II In-source hydrolysis, 28 Intelisite capsule, 182 International Conference on Harmonization

(lCH),4 Interspecies scaling, 133, 137 Intestinal absorption, 56, 196 Intestinal eft1ux, 55, 179, 186 Intestinal metabolism, 180 Intestinal transit, 55-56 Intestine, 55 Intrinsic clearance, 97, 154-155 Investigator's brochure. 1-2 IR,191 Irbesartan. 539 Isolated perfused liver, 86 Isomers. 32 rvIVC,64,157,227,229-231 IX-SPE.32

Jejunum, 56, 181

K.,336,379 Kaletra, 329 Kallynochrons, 142 K." 336 K..,346 Ketamine, 533 Ketoconazole.318 1(;,309.311 K...309 Kp,153

Labeling. 195,323 Labile. 38 Lactation, 267, 274 LCIMSIMS,23 LCM,187 Lead identification, 8 Lead optimization, 8 Lidocaine therapy, 493 Line extension, 225, 365 Linear model, 339, 355 Link model, 357 Linked pharmacodynamic models, 500 Lipinski's Rule of Five, 66 Liposomal, 10 Liquid scintillation counting, 45 Liver

microsomes,35 necrosis, 94 slices. 85

Local minima, 374

547

548

~ log D,68 LogP, 66 Logistic regression, 345 Log-likelihood, 374 Log-linear, 339, 355 Lopinavir, 328 Lorazepam, 532 Losartan,538 Low clearance drugs, 96 LY303366,216 Lysylpyridinoline,447

MALDI,38 MAP, 374,483 Matrix, 96 Matrix effects, 36 Maturation, 251 Maximum life span, 99 Maximum likelihood, 385 MDR,I64 Meal,I95 Meal type, 204 Meal viscosity, 204 Mechanism-based inactivation, 113 Metabolic

clearance, 154 profiling, 77 stability, 77

Metabolism dependent inhibition, 113 Metabolite, 21

identification, 89 quantitation, 29 standards, 30

Methadone, 534 Methylprednisolone, 356 Mibefradil, 113 MIC,336 Microsomal protein, 98 Microsome, 83 Midazolam, 259, 318, 532 Mivacurium, 530 MLP, 143, 159 MLR,65 Model,54 Model misspecification, 377 Model validation, 358 Modeling and simulation, II, 14 Modeling drug diffusion, 500 Modified release, 233 Morphine, 534 MRI,8,I0 MRP,206 Multiple model, 523

Nanotechnology, 8,10 NDA, 2, 76, 209 Nefazodone, 325 Neider-Mead, 354 New molecular entity (NME), I, 185 N-in-I, 29, 87 Nitrazepam, 281 NMR,30--31 NOAEL, 167

Non-clinical,2 Noncompartmental,335 Non-linear pharmacokinetics, 86 NONMEM, 354, 375 Nonparametric model, 383-384 NPAG,390 NPEM,386 NPML, 386 NSAIDs,405 NTI, 229, 232 NTR.232

OATP, 164,308 OCT,I64 Omapatrilat, 39 Omeprazole, 279, 540 Oral drug product, 196 Organ impairment, 246, 263 Osteocalcin,447 Osteoporosis, 427, 430 Oxazepam, 532

Paget's disease, 428 Pancuronium, 530 Paracellular, 56, 179,200 Paracetamol, 36 Parallel tube model, 62 Parameter space, 395 Parametric population modeling, 374 Parkinson's disease, I PBPK, 133,134 Pediatric drug fonnulation, 254 Pediatric labeling, 259 Pediatrics, 246, 247 Pelf, 57, 61 Perfusion rate limited, 134 Peristaltic waves, 55 Permeability, 55,60, 196, 198,226,236 Permeability coefficient, 136 Permeation, 179 PET,8,lO

INDEX

p-glycoprotein (or Pgp; see Transporter), 179, 180,206,308,314

Pharmacodynamic, 3,333 Pharmacoeconomics,4 Pharmacoepidemiology, 4 Pharmacogenetics, 8 Pharmacogenomics, 8 Pharmacokinetic,3,333 Pharmacology/toxicology, 6 Phase I enzymes, 77, 82 Phase II enzyynes, 77,79,82 Phenobarbital, 533 Phenytoin, 80--81,212 Physiological time scales, 140 Physiologically based direct scaling, 156 Pioglitazone, 324 Pipecuronium,530 PKJPD,I0--12,333,351,374,481 pKa,32 Plasma drug concentration, 12 Plasma protein binding, 13 Polymorphism, 102

INDEX

Poor metabolizers, 102 Population, 373 Population PKlPD, 7,481 Post-column photolysis, 36 Post-marketing studies, 4, 361 Potency, 63 Power, 355 PPAR,119 Pravastatin,40 Pre-clinical development, 2, 76, 361 Pregnancy, 267,273 Pre-IND,2 Pre-NDA meeting, 2 Probe inhibitors, 310 Probe substrates, 3 I 0, 3 15 Probenecid, 41 Product extension, 4 Product labeling, 245 Proof of concept, 360 Protein binding, 137 Protein meals, 200 Protein precipitation, 36 PXR,119

QSAR,54,66 QSBR, 54, 65, 68, 70 QT prolongation, 307

R, S-enantiomer, 41 Reaction phenotyping, 77, 85,101,312 Reactive metabolites, 77 Reactive thiol. 39 RBC/plasma partitioning, 39 Receptor binding, 13 Region-dependent absorption, 207 Regioselectivity, 83 Remifentanil, 40 Renal clearance, 165 Renal function. 283 Renal impairment, 282 Residence time, 56 Retention time. 28 Rezulin (troglitazone), 120 Rifampicin. 537 Ritonavir, 213 Rivastigmine. 264, 531 Roxifiban, 31-33 Roxifiban metabolites. 31-35 Run times, 23

S9.35 St. John's wort. 320. 326-327 Saquinavir. 213 Saturable. 57 SAX. 32 Scaling factors. 98 Schwartz criteria. 355 Selectivity. 22 Selegiline. 536 SELEX.IO Sensitivity. 22 Separation principle. 383 Sex. 246

Sigmoidal Emax, 340, 357 Sigmoidicity. 507 Sildenafil, 325 Soft link, 343 Solid dosage form, 226 Sparse sampling, 13 Special populations. 245 Specificity. 22 SPECT, 8.10 SRM.25 Stable isotope internal standards, 32 Standard two-stage, 374 Starting dose. 167 Stationary phase, 24 Structural model, 353 Subcellular fractions, 83 Sufentanil, 531 Suicide inhibition, 113 SUPAC, 227-228, 233 Surrogate end points. 9, 338, 351

Tamoxifen. 36 Target-oriented. model-based approach, 487 Temporal, 12 TGA.31 Therapeutic drug monitoring. 495 Therapeutic index. 364 Therapeutic range, 478 Tight junction. 56 Time invariant. 344 Time variant, 344 Tissue binding. 151 Tissue-to-plasma, 137 TOF,44 Tolerance model, 344 Toxic metabolite. 90 Toxicokinetics, 3 Toxicology. 2. 3 Transcellular, 56-57, 179 Transporter, 54. 313 Transporter/absorption. 9 Triazolam, 533 Triple-quadrupole technology, 22 Troglitazone. 77 Trough. 13 Tubocurarine, 530 Two-peak. ranitidine. 58

Ultrarapid metatabo lizers. 102 Unbound drug. 137 Unstable metabolites. 38 Urinary hydroxyproline. 441 US FDA (see FDA). 5 USC*PACK. 375. 377

Valdecoxib.324 Vancomycin therapy. 490 Vecuronium.530 Verapamil.540 Vrnax,97 VODE.382 Vss.151 Vssu.153

549

550 INDEX

Warfarin, 355 Well stirred model, 62 Women in bioequivalence studies, 268

Xenobiotic, 76

Zwitterion, 31-32