1. John N. van den Anker, MD, PhD
The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects
John N. van den Anker, MD, PhD
Evan and Cindy Jones Chair in Pediatric Clinical Pharmacology
Professor of Pediatrics, Pharmacology & Physiology, GWU, Washington, DC
Chief, Division of Pediatric Clinical Pharmacology, Children’s National, DC
Adjunct Professor of Medicine, Pediatrics, Pharmacology & Physiology
Johns Hopkins University, Baltimore, MD

2. “ Pediatrics does not deal with miniature men and women, with reduced doses and the same class of diseases in smaller bodies, but….it has its own independent range and horizon…”
Dr. Abraham Jacobi, 1889

3. Critical Role of Drug Disposition in Pediatric Therapeutics
Age-dependent PD data in similar disease
processes
The combination of absorption, distribution, metabolism & elimination determine drug exposure
drug exposure determines drug response
Knowledge of the relationship between PK and exposure dictates dose
Safety/tolerance data with therapeutic use
Rational Therapeutics
Acceptable formulations
Age-dependent PK data to guide dose/exposure

4. Absorption
Oral
Sublingual
Intramuscular
Percutaneous
Rectal

5. Factors Influencing Oral Drug Absorption
Splanchnic
blood flow
Biliary
function
Gastric pH
Gastric
emptying time
Intestinal drug
metabolism
Physicochemical
&
Mechanical
Intestinal
motility
Intestinal
surface area
Microbial
colonization
Intestinal
drug transport

6. Developmental Alterations in Gastric pH
% Adult Activity
birth
1 wk
2 wk
3 wk
1 mos
3 mos
5-10 yr
adult
HCl production
Pepsin
Gastrin 50
100
150
200
250
Agunod et al. Amer J Digest Dis 1969;14:400
Mozam et al. Ann Surg 1984;199:389
Rodgers et al. J. Pediatr Surg 1978;13:13

7. Orally Administered Penicillin (10,000 U/lb)
Influence of Developmental Alterations in Gastric pH
Orally Administered Penicillin (10,000 U/lb)
0.5 1
1.5 2
2.5 3
3.5 4 6 8
Time (hr)
Penicillin concentration (U/mL)
Preterm neonate
Fullterm neonate
Infants (2 wk-2 yr)
Children (2-13 yr)
Huang et al. J Pediatr 1953;42:657

8. Developmental Alterations in Gastric Emptying Rate
Pre-term
Full term
30 minute gastric retention 10 20 30 40 50 60 70
4-12 hr
22-36 hr
46-60 hr
Postnatal Age
% of meal
Gupta & Brans, Pediatrics 1978;62:26

9. Plasma Concentration (ng/mL)
Influence of Developmental Alterations in Gastric Emptying & Intestinal Transit
Single-Dose Cisapride PK in Neonates and Young Infants
Plasma Concentration (ng/mL) 5 10 15 20 25 30 35
Time (hr)
28-36wk ( )
36-42wk ( )
42-54wk ( )
PCA -- Tmax (hr)
Adult (1.8)
Kearns, van den Anker, et al. Clin Pharmacol Ther 2001;69:31

10. Getting the drug in…
Do you have an age appropriate pediatric formulation?
newborn
infant
preschool
school-aged
adolescent
solid oral
chewable
oral liquid
rectal
transdermal
parenteral
intranasal
intraocular

11. Orifice rejection of drugs is the rule rather than the exception.
Developmental Alterations in Oral Drug Absorption
1st Law of Pediatric Drug Administration
Orifice rejection of drugs is the rule rather than the exception.

12. Diffusional surface area Temperature Hydration Local pH
Factors Influencing Transdermal Drug Absorption
Barrier thickness
Regional blood flow
Diffusional surface area
Temperature
Hydration
Local pH
Tissue binding sites
Drug-vehicle interactions

13. Developmental Alterations in Skin thickness
GA: 26 wk
PNA: 1 day
GA: 26 wk
PNA: 16 days
GA: 40 wk
PNA: 1 day
Rutter. Clin Perinatol 1987;14:911

14. Impact of Enhanced Skin Permeability on Cutaneous Absorption
Neonatal Case Reports
Agent
Resultant ADR
silver sulfadiazene
cardiorespiratory arrest
topical steroids
HPA suppression
cushingoid features
pentachlorophenol
(laundry detergent)
diaphoresis
hepatomegaly
acidosis
boric acid
(talcum powder)
death

15. Volume of Distribution

16. Age Dependent Changes in Body Composition
EC H2O
IC H2O
Protein
Fat 20 40 60 80
100
Premature
Newborn
4 mo
12 mo
24 mo
36 mo
Adult

17. Impact of Changes in Extracellular Fluid on Drug Distribution
0.5 1
1.5 2
2.5 3
3.5
0.5-5 yr
5-10 yr
10-15 yr
15-42 yr
Age
Peak Gentamicin Concentration
(mg/L per mg/kg dose)
Siber et al. J Infect Dis 1975;132:637

18. Drug biotransformation
Phase I
Phase II
Drug
Metabolite
Metabolite
UGTs
NATs
SULTs
MTs
GSTs
CYPs
FMOs
Esterases
Hydrolases

19. Human Hepatic DME Ontogeny
Class 1
SULT1A3
CYP3A7
SULT1E1
GSTP
ADH1A
FMO1
Class 2
CYP3A5
SULT1A1
GSTA2
CYP2C19
GSTA1
Class 3
CYP2E1
UGT2B7
CYP2D6
UGT1A6
FMO3
ADH1C
CYP2C9
UGT1A1
CYP1A2
SULT2A1
EPHX1
ADH1B
EPHX2
CYP3A4
PON1
GSTM
AOX
Hines, Pharmacol & Therap. 118: , 2008 19

20. Human DME Ontogeny DME (pmol/mg protein) 10 20 30 40 SULT1E1 Class 110 20 30 40
SULT1E1
Class 1
SULT1A1
Class 2
CYP2C9
Class 3
EGA
10-26 wks
>26-40 wks
PNA
0-6 mo
>6 mo-18 yr 20

21. Ontogeny of CYP2C19 In Vitro
EGA (Weeks)
PNA (Months)
PNA (Years) 3 6 9 12 15 18 14 22 30 38 1 2 4 5 40 20 10
CYP2C19 Protein (pmol/mg)
Koukouritaki et al J Pharmacol Exp Ther 2004;308:

22. Ontogeny of CYP2C19 In Vivo
Postmenstrual Age
Postnatal Age
r2 = 0.35
Ward et al Eur J Clin Pharmacol 2010;66:

23. APAP Biotransformation in Humans
APAP-G
UGT1A6
UGT1A9
Ratio Gluc:Sulf
Mean  SE
Newborns
N=4
0.340.08
3-9 yr
N=7
0.750.10
12 yr
1.610.21
Adults
1.801.32
SULT1A1
APAP
APAP-S
CYP3A4
CYP1A2
CYP2E1
NAPQI
Mercapturate
Miller, et al. Clin. Pharmacol. Ther. 19: , 1976

24. APAP t1/2 min (IV paracetamol)
Impact of Developmental Alterations in Phase II Enzymes on Drug Metabolism: Acetaminophen
126
days (n=7)
210
term <10 days (n=5)
265
Preterm wk (n=10)
290
Preterm <32 wk (n=10)
APAP t1/2 min (IV paracetamol)
Age
Allegaert, et al. Arch Dis Child Fetal Neonatal Ed. 2004;89:25-28

25. Developmental Alterations in Glomerular Filtration10 20 30 40 50 60 70
1-2 d
8-9 d
15-16 d
GFR (ml/min/1.73m2)
Postnatal Age
Term
Preterm (<2000gm)
Preterm (<1500 gm)

26. Impact of Developmental Alterations in Renal Function on Drug Elimination
clearance
(ml/min/kg)
half-
life
(hr)
premature 1 day
0.18
88.6
premature 7 days
0.33
67.5
premature 13 days
0.52
55.2
Fluconazole
infants
< 29 wk, <14 d
q72hr
< 29 wk, >14 d
q48hr
30-36 wk, <14 d
30-36 wk, >14 d
q24hr
Saxen, et al. Clin Pharmacol Ther 1993;54:269

27. OATP2, OATP8, OATP-B, OCT1, NTCP,
Biliary Excretion
P-gp, MRP3, MRP2, sPGP
Hepatic Uptake
OATP2, OATP8, OATP-B, OCT1, NTCP,
OAT2, OAT3
Intestinal Efflux
P-gp, MRP2, MRP1,
OCT1, OATP3,
NTCP
Brain Transport
P-gp, OAT3,
MRP1, MRP5,
OATP1
Renal Secretion
OAT1, OAT3, OCT1,
OCT2, OATP,
P-gp, MRP1
Ritschel WA and Kearns GL. Handbook of Basic Pharmacokinetics, 7th edition, 2009

28. Pediatric Clinical Pharmacology Facts
Children are not small adults
different pharmacokinetics
different pharmacodynamics
Approximately 70% of all marketed drugs not suitably labeled for pediatric use
In some instances, pediatric patients included in studies as an “afterthought”
The biggest issue remains determining the effective/safe dose for pediatrics

30. The In-silico Child…….

31. Considering protocol elements…
Are elements of the protocol nonsensical ?
Required consent language:
If the patient is a female of child bearing potential, she must not be a pregnant or nursing…...
If she is sexually active, she will be required to take precautions to avoid the possibility of becoming pregnant for up to 30 days past study drug ingestion. The use of oral contraceptives, ……intrauterine devices, barrier method (condom plus diaphragm, or condom plus contraceptive sponge, or condom plus intravaginal suppository) are accepted methods of birth control.. ….
A pregnancy test will be done at the start of the study
neonatal pharmacokinetic study

32. Measuring drug concentrations…
Consider the allowable blood volume that can be drawn for the study (PK and safety labs).
ICH E11 defers to IRB/IEC
age
weight
circulating blood volume
max allowable q2wk
PT neonate
500 g
40 mL
1.5 mL
FT neonate
4 kg
320 mL 12
infant (3 yr)
15 kg
1.2 L 45
child (12 yr)
40 kg
3.2 L
120
Have microassays been developed & validated?
Is a sparse/minimal sampling scheme appropriate?

33. Designing a Pediatric Protocol
Selecting the population
Selecting the dosing scheme
Getting the drug in
Measuring drug concentrations
Monitoring tolerability/safety
Analyzing data
Considering protocol elements

35. Courtesy of Dr. Catherine Tuleu, Univ. of London, 2011

36. CONCLUSIONS
TEAM WORK