DEVELOPMENTAL PK/PD: WHAT HAVE WE LEARNT? Geoff Tucker
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