First in Child Studies With New
Drugs:
How to Find the Appropriate Age-Related Dose for Minors?
Willi Weber
Sanofi-Aventis
13 Jan 2009
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Part IV
Pharmacometrical Considerations on
Covariates: Weight, Age, Gender, Metabolic
Conditions, . . .
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
1
Covariates & Dose Finding
Explain Variability of Drug Effects
2
Growth & Maturation
Comparison with Adults
Clinical Data
3
Conclusion
4
Backups
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Explain Variability of Drug Effects
Target Concentration → Target Effect
DosingRate =
Dose
τ
Cmax =
= Target ×
CL
F
Dose/Vd/F
−τ /t1/2
1−2
Cmax=8mg/L → Cmin=2mg/L → Dose interval τ = 2t1/2
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Explain Variability of Drug Effects
Explaining Variability between Dose & Effect
τ, F
CL, V
d
Dose −−−→ C(t) −−−−→
Effect(D50 , Emax )
Weight, Obesity, Growth → CL, Vd
Age, Maturation & Growth → F, CL, Vd, D50 , Emax
Gender → CL, Vd
Metabolic Conditions, Hepatic Disease → F, CL
Kidney Disease → CL, Vd, D50 , Emax
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Comparison with Adults
Clinical Data
Difference between Children & Adults: Growth
Hypothesis
Scale down from adults
to adolescents
to Cyp mature children
above 2 (above 6?) yrs
to infants, neonates?
Neonate ∼ small Adult?
PK Simulation using . . .
fixed Weight effect
Willi Weber
Clearance ∼ Weight 0.75
Volume ∼ Weight 1.0
Covariates in Pharmacometrics
HalfLife ∼ Weight 0.25
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Comparison with Adults
Clinical Data
Neonates, Infants: Maturation & Growth
Neonate ∼ no small Adult?
Hypothesis
Include AGE dependent Maturation
into the PK model!
PK Simulation using . . .
fixed Weight & fitted AGE effect
Clearance ∼ Mat(AGE )Weight 0.75
Volume ∼ Body (AGE )Weight 1.0
Maturation Time Course → 1
Mat(AGE,∆Emax , EAge50 )
Willi Weber
HalfLife ∼
Weight 0.25 Body (AGE )
Mat(AGE )
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Berlin
South France
Comparison with Adults
Clinical Data
2.32*exp(.095*(APC-35.7) kg
1.83*exp(.110*(APC-36.7) kg
Growth of Neonates: Berlin - South France
●
4.0
●
3.5
●
●
Weight (WT)
●
3.0
●
2.5
●
2.0
1.5
●
●
●
●
32
34
●
●
●
●
●
●
●
36
38
40
Post Conceptual AGE (APC)
Willi Weber
42
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Comparison with Adults
Clinical Data
Kidney Maturation
Creatinine clearance vs conceptional age
children (0.5 - 20 yrs) = 120 ml/min/1.73m2
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Comparison with Adults
Clinical Data
Kidney Maturation Completed after 6 to 12 Month
Creatinine clearance vs conceptional age
TMAT 50,weeks = 36 + 16 ± 30%,
CLCRmax = 120 ml/min/1.73m2
Maturation
100
80
CLCR
60
40
20
0
10
20
30
40
50
Post Natal Age
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Comparison with Adults
Clinical Data
Bayesian Estimate of PK: PopPK & Conc(Time, Dose)
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Comparison with Adults
Clinical Data
Metabolic Condition: Fast Maturation first 3 Month!
Metabolism: Maturation of
drug metabolizing enzymes
Phase I
Cytochrome P450 enzymes
Phase II
Sulfation
Acetylation
Glucuronidation
Conjugation
with glycin
0
20 40
1
2
3
4
months of life
weeks of
gestation
Willi Weber
modified acc. to Seyberth et al.
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Conclusion
Children Growth & Maturation - Adults both finished
Maturation → 2 yrs: Age Classification - premature -,
neonates, infants, toddler
Growth 2 → 18 yrs: 10 < 50 < 100 kg
1/4 < 3/4 < 5/4 scaling factors compared to 70 kg
subject, 2 WT groups with a ful and half the adult dose
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Learning & Confirming
PK: Simulate < −− > Observe
1
2
3
4
5
6
scale CL (WT /70)3/4 assume CV variability (adults)
if required apply maturation Hill(AGE)!
estimate dose to achieve target concentration (adults)
PK simulation e.g. CLWT (AGE ) ±40%
confirm PK in a pilot study: dose a single child
use Bayesian CL estimate for another simulation
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Conclusion
Children Growth & Maturation - Adults both finished
Growth - WT = f(AGE)
Maturation - Kidney, Liver Function = f(AGE< 2yrs)
WT used for scaling, Maturation AGE dependent until 2
yrs - WT or AGE classification
avoid COLLINEARITY, use either WT or AGE and
calculate one from the other
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Growth dominant effect above 2 yrs
between 2 and 12 yrs mainly growth effects
gender differences during puberty
the adult body is mature, growth stopped
size dependent on gender - epiphysis closure
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Maturation & Growth up to 2 yrs
maturation and growth are fast in premature -, neonates
& infants below 2 yrs
between 2 and 6 yrs CYP enzyme pattern of the liver
similar to adults
kidney function approach adults 120 ml/min/1.73 m2
6 month after birth
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Collinearity of Demographic Covariates
30
●
●
●
●
●
●
●
WT
3.5
●
●
●
●
1.5
2.5
●
●
| ||| |
|
| || |
●
●
●
●
●
● ●●
●
●
●
●
●
●
HT
●
●
●
●
●
●
●
●
●
●●
●
●
●
● ●
●
●
● ● ●
●
●
●
●
●
●
●
|
● ●
●
●
●
●
●
●
●
●
●
● ●
●
●
●
●
●
●
||
●
●
●
●
●
●
●
● ● ●
●
●
●
●
●
●
●
●
●
●
●
50
| | | | |
●
●
●
●
90
45
|| | | |
70
●●
●
●
●
●
●
●●
●●
●
●
50
●
●
40
●
● ●
●
36
●
●
32
3.5
●
●
|| | |
||| || |
●
●
●
40
2.5
●
35
1.5
APC
●
90
CREA
70
● ●
●●
●
50
●
●
●
●
● ●
●●
●
●
●
● ●
●
●
32
36
●
●
●
●
30
●
●
●
●
●
40
●
●
●
●
●
●● ●
●
35
Willi Weber
●
40
45
| ||||
| | | |
|
50
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Classical Pharmacokinetic Evaluation
Standard Two Stage, STS
Willi Weber
Covariates in Pharmacometrics
Covariates & Dose Finding
Growth & Maturation
Conclusion
Backups
Population Pharmacokinetics
Nonlinear Mixed Effect Modeling - NONMEM
Willi Weber
Covariates in Pharmacometrics