DEVELOPMENTAL PK/PD:WHAT HAVE WE LEARNT?

Geoff Tucker

UNDERSTANDING AND PREDICTING PK/PD IN JUVENILES

Can we scale from juvenile animals?

Can we scale from allometry?

Can we scale from in vitro?

PHARMACOKINETICS

ORAL BIOAVAILABILITY

From Grass & Sinko

(Adv Drug Deliv Rev,2002) from Sietsema

(Int J Clin

Pharmacol Ther Toxicol,1989)

20

40

60

80

100

0neonate infant child adolescent adult

% Adult

♂RAT CYP3A1(Johnson et al, 2000)

♀RAT CYP3A1(Johnson et al, 2000)

DOG CYP3A12(Taneka, 1998)

HUMAN CYP3A4(Johnson et al,2006)

ONTOGENY OF TRANSPORTERS (ANIMALS)weaning

Live

rIn

test

ine

Kid

ney

PgP

–

MOUSE (Mahmood

et al, 2001)PgP

–

RAT BRAIN(Matsouka

et al, 1999)

OATs

–

RAT KIDNEY(Buist

et al, 2002)

Bile salt/OATs

–

RAT LIVER(Gao

et al, 2004)

Can we scale from juvenile animals?

Can we scale from allometry?

Can we scale from in vitro?

PHARMACOKINETICS

“THE 3/4 (Klieber’s) LAW”

From allometric

principles:

Metabolic Rate ∝

BW0.75

Clearance ∝

BW0.75

Holford

–

“A size standard for pharmacokinetics”Clin Pharmacokin 30: 392-32, 1996

“THE 3/4 (Klieber’s) LAW”

Liver Volume = 0.722 x BSA1.176

Liver Volume ∝

BW0.78

Johnson et al –

“Changes in liver volume frombirth to adulthood: a meta-analysis”Liver Transpl 11: 1481-93, 2005

From measurements in 5036 N.Europeans, N.Americans

and Japanese:

BSA ∝

BW0.67

Clearance ∝

BW0.78

:

00.2

0.40.6

0.81

1.21.4

1.6

0 20 40 60 80

Body weight (kg)

Live

r Si

ze (L)

Johnson et al: LV=0.722 x BSA1.176

Allometric: LVchild

=LVadult

x (BW/70kg)0.75

0

0.4

0.8

1.2

1.6

10 20 30 40 50 60 70

Liver Volume (L)

Body Weight (kg)

LV = 0.722 x BSA1.176

LV = 1.46 x (BW/70kg)0.75

(n = 162 patients)

Fanta

et al – “Developmentalpharmacokinetics of ciclosporin:A population pharmacokineticstudy in paediatric transplantpatientsBr J Clin Pharmacol 64:772, 2007

The ‘3/4 Rule’

holds for predicting the clearance of several drugs (e.g.CYP3A substrates–

ciclosporine, midazolam, alfentanil

etc)

But it does not account for the ontogeny of drug metabolising enzymes in neonates and infants.

Use ‘3/4 Rule’

to normalise clearance only > 2 years.

Can we scale from juvenile animals?

Can we scale from allometry?

Can we scale from in vitro?

PHARMACOKINETICS

AGE-RELATED CHANGES IN CYP EXPRESSION/ACTIVITY

Johnson et al (2006)

1A2 2B6

2C8 2C9

2C19 2D6

2E1 3A

EFFECT OF DIET ON CAFFEINE ELIMINATION RATE CONSTANT(CYP1A2)

Blake et al (2006)

GLUCURONIDATION

Time to maturity?

UGT1A1

UGT1A9UGT2B4UGT2B7

UGT1A4< 6 months

> 2 years> 2 years< 6 months

< 2 years

Strassburg

et al, 2002; Miyagi & Collier, 2007

(e.g. ethinylestradiol

(e.g. imipramine)

(e.g. propofol)

(e.g. morphine)

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 20 40 60 80 1000

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0.4

0 20 40 60 80 100

0

0.5

1

1.5

0 20 40 60 80 1000

0.5

1

1.5

0 20 40 60 80 100

0

1

2

3

4

5

6

7

0 20 40 60 80 1000

1

2

3

4

5

6

7

0 20 40 60 80 100

0

0.2

0.4

0.6

0.8

1

1.2

1.4

0 20 40 60 80 1000

0.2

0.4

0.6

0.8

1

1.2

1.4

0 20 40 60 80 100

00.5

11.5

22.5

33.5

44.5

0 20 40 60 80 1000

0.51

1.52

2.53

3.54

4.5

0 20 40 60 80 100

0

0.05

0.1

0.15

0.2

0.25

0 20 40 60 80 1000

0.05

0.1

0.15

0.2

0.25

0 20 40 60 80 100

0

0.002

0.004

0.006

0.008

0.01

0.012

0.014

0.016

0 20 40 60 80 1000

0.002

0.004

0.006

0.008

0.01

0.012

0.014

0.016

0 20 40 60 80 100

CL

(L.k

g.h)

Weight (kg)

Omeprazole (Oral)

0

0.05

0.1

0.15

0.2

0.25

0.3

0.35

0 20 40 60 80 100

Carbamazepine(Oral)

Phenytoin (Oral)

Midazolam (Oral)

Diclofenac (IV)

Cisapride (Oral)

Theophylline (Oral)

S-Warfarin (Oral)

0

0.5

1

1.5

2

2.5

0 20 40 60 80 100

Midazolam (IV)

0

0.5

1

1.5

2

2.5

0 20 40 60 80 100

Midazolam (IV)

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0 20 40 60 80 100

Caffeine (Oral)

0.00

0.10

0.20

0.30

0.40

0.50

0.60

0 20 40 60 80 100

Caffeine (Oral)

Johnson et al.Clin

Pharmacokin

2006

Predicting PaediatricClearance

Below ~ 2years –

prediction of clearance is drug specificdue to differential development of its determinants.

Full Paediatric PBPK Model

•

Incorporating information on organ size, tissue composition and blood flow

•

Allows for prediction of full PK profile (V, MRT, Cmax

, Cmin

)

Veno

us B

lood

Art

eria

l Blo

od

LungLung

AdiposeAdipose

BoneBone

BrainBrain

HeartHeart

KidneyKidney

MuscleMuscle

SkinSkin

LiverLiver

SpleenSpleen

GutGut

Portal Portal VeinVein

PO IV

Veno

us B

lood

Art

eria

l Blo

od

LungLung

AdiposeAdipose

BoneBone

BrainBrain

HeartHeart

KidneyKidney

MuscleMuscle

SkinSkin

LiverLiver

SpleenSpleen

GutGut

Portal Portal VeinVein

PO IV

0200400600800

10001200140016001800

0 5 10 15

Age (y)

Bra

in W

eigh

t (g)

Ogiu et alICRP

ORGAN SIZE

01020304050607080

0 2 4 6 8 10 12 14

BB

F (L

.h)

0102030405060

0 2 4 6 8 10 12 14Age

RB

F (L

.h)

Renal

Age (y)

Brain

020406080100120

0 5 10 15 20Age (y)

Qh

(L.h

)

Liver

0102030405060

0 4 8 12 16Age (y)

Mus

cle

BF

(L.h

)

Muscle

048121620

0 4 8 12 16Age (y)

Skin

BF

(L.h

)

Skin

0510152025

0 4 8 12 16Age (y)

Adi

pose

BF

(L.h

)

Adipose

ORGAN BLOOD FLOWS

Lung

0102030405060708090

0 5 10 15 20

Muscle

0102030405060708090

0 5 10 15 20

Adipose

010203040506070

0 5 10 15 20

Skin0

102030405060708090

0 5 10 15 20

Liver0

102030405060708090

0 5 10 15 20% W

ater Kidney

0102030405060708090

0 5 10 15 20

Heart0

102030405060708090

100

0 5 10 15 20

Brain

0102030405060708090100

0 5 10 15 20

Bone010203040506070

0 5 10 15 20

Spleen

0102030405060708090

0 5 10 15 20

Plasma

0102030405060708090

100

0 5 10 15 20

Age (y)

GI tract0102030405060708090

0 5 10 15 20

TISSUE COMPOSITION -

WATER

Skin fixed 3.95%

Lung0

0.51

1.52

2.53

3.54

0 5 10 15 20

Adipose01020

30405060708090

0 5 10 15 20

Muscle

00.511.522.533.54

4.5

0 5 10 15 20

Liver

012345678

0 5 10 15 20

Kidney

0123456

0 5 10 15 20

Heart

01234567

0 5 10 15 20

Brain

02468

101214

0 5 10 15 20

% fa

t

Bone012345678

0 5 10 15 20

Spleen0

0.51

1.52

0 5 10 15 20

Plasma0

0.10.20.30.40.50.60.70.8

0 5 10 15 20Age (y)

GI tract01234567

0 5 10 15 20

TISSUE COMPOSITION -

FAT0

50100150200250300

0 4 8 12Age (year)

GFR

(ml/m

in/1

.73m

2 ) Female Male

RENAL FUNCTION

Alb = 1.1287Ln(t) + 33.746 0.38D

0.38

0.38D

g/L Age8.89Age0.887AAG+×

=

0

10

20

30

40

50

60

0.1 1 10 100 100010000100000

Age (days)

Alb

umin

(g/L

)

00.2

0.40.6

0.81

1.21.4

0.1 1 10 100 100010000100000Age (days)

AA

G (g

/L)

PLASMA PROTEINS

0

50

100

150

200

Birth1wk 2wk 3wk 1mo 3mo 1-3y 4-6y5-10yAdult

HCl

productionBile acid secretionIntestinal length

% AdultGASTROINTESTINAL

FUNCTION

PK MODELLING“TOP DOWN”

“BOTTOM UP”

Demography, Physiology, Genetics,

In Vitro Data

POPPK

PBPK/IVIVE

Confirming

Learning

Plasma Data

PHARMACODYNAMICS

Age-Related Changes in Concentration-Reponse

Drug Age Range n Observation Reference

Cyclosporin 3mo –

39y 56 Increased CReffect in <1-4ygroup

Marshall & Kearns (1999)

Warfarin 1 –

76y 134 Increased CReffect (INR/dose)in 1-11y group

Takahashi et al (2000)

Midazolam Preterm –

29w 31 Decreased CR(sedation)

De Wildt

et al (2001)

0

5

10

15

20

25

3 10 21

Latency to right (secs)

Postnatal Age (days)

Koch et al (2008)

MIDAZOLAM (10mg/kg S/C –

Rats)

BaselineAfter midazolam

“Dynamic mapping of human cortical development duringchildhood through early adulthood”Gogtay

et al –

PNAS 101: 8174, 2004

“Contribution of midazolam

and its 1-hydroxy metaboliteto preoperative sedation in children: a pharmacokinetic-

pharmacodynamic

analysis”

Johnson et al: Br J Anaesth 89:428, 2002

PK-PD MODELLING

“A 50% increase in dose would increase odds ratio from 4 to 275

in favour of sedation score 2 (drowsy/asleep) at start of

surgery”

-

Homocysteinuria(3 in 1 million)

-

Betaine(orphan drug)

-

Limited population of patients to study

-

No Pharma

funding for large studies

Solution:Clinical Trial Simulation

Br J Clin Pharmacol 54:140,2002

Methionine

Homocysteine

S-

Adenosylhomocysteine

Cystationine beta-synthase

Betaine

N,N.DimethylN,N. glycine

kin

– kout

S(t) H(t)=dtdH

S(t) =)(

)(150 tCEC

tCE

Betaine

BetaineMax+

+

Ove

rall

redu

ctio

n in

Increase in the usual daily dosage (150 mg/kg) or in dosage frequency greater than twice daily is predicted to give negligible added clinicalbenefit for an additional cost of £2100 per patient year and potential decrease in compliance.Two

divided daily doses may be optimal.

Concentrate on < 2 year olds-

More variable

-

High risk-

Developing systems

More ‘creative’

PD evaluation