John N. van den Anker, MD, PhD

The Design of Pediatric Clinical Trials and the Relevant Scientific and Methodological Aspects

Evan and Cindy Jones Chair in Pediatric Clinical PharmacologyProfessor of Pediatrics, Pharmacology & Physiology, GWU, Washington, DCChief, Division of Pediatric Clinical Pharmacology, Children’s National, DCAdjunct Professor of Medicine, Pediatrics, Pharmacology & PhysiologyJohns Hopkins University, Baltimore, MD

“ 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

Critical Role of Drug Disposition in Pediatric Therapeutics

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 Age-dependent

PK data to guide dose/exposure

Age-dependent PD data in similar

disease processes

Safety/tolerance data with

therapeutic use

Acceptable formulations

Rational Therapeutics

Absorption

Oral

Sublingual

Intramuscular

Percutaneous

Rectal

Factors Influencing Oral Drug Absorption

Biliary function

Physicochemical&

Mechanical

Gastric pH

Intestinal drug

metabolism

Gastric

emptying time

Intestinal

motility

Intestinal

surface area

Splanchnic

blood flow

Microbial

colonizationIntestinal

drug transport

Developmental Alterations in Gastric pH

Agunod et al. Amer J Digest Dis 1969;14:400Mozam et al. Ann Surg 1984;199:389Rodgers et al. J. Pediatr Surg 1978;13:13

% A

du

lt A

ctiv

ity

birth1 wk

2 wk3 wk

1 mos3 mos

5-10 yr adult HCl productionPepsin

Gastrin

0

50

100

150

200

250

Influence of Developmental Alterations in Gastric pH

Huang et al. J Pediatr 1953;42:657

Orally Administered Penicillin (10,000 U/lb)

0

0.5

1

1.5

2

2.5

3

3.5

0 2 4 6 8

Time (hr)

Pen

icill

in c

once

ntra

tion

(U/m

L) Preterm neonate

Fullterm neonate

Infants (2 wk-2 yr)

Children (2-13 yr)

Developmental Alterations in Gastric Emptying Rate

Gupta & Brans, Pediatrics 1978;62:26

Pre-term

Full term

30 minute gastric retention

0

10

20

30

40

50

60

70

4-12 hr 22-36 hr 46-60 hr

Postnatal Age

% o

f mea

l

Pla

sma

Con

cent

ratio

n (n

g/m

L)

0

5

10

15

20

25

30

35

0 5 10 15 20 25Time (hr)

28-36wk (5.0 + 2.6)36-42wk (4.3 + 3.3)42-54wk (2.2 + 1.1)

PCA -- Tmax (hr)

Adult (1.8)

Kearns, van den Anker, et al. Clin Pharmacol Ther 2001;69:31

Influence of Developmental Alterations in Gastric Emptying & Intestinal Transit

Single-Dose Cisapride PK in Neonates and Young Infants

Getting the drug in…

Do you have an age appropriate pediatric formulation?

solid oral

chewable

oral liquid

rectal

transdermal

parenteral

intranasal

intraocular

newborn infant preschool school-aged adolescent

Developmental Alterations in Oral Drug Absorption

1st Law of Pediatric Drug Administration

Orifice rejection of drugs is the rule rather than the exception.

Factors Influencing Transdermal Drug Absorption

Barrier thickness Regional blood flow Diffusional surface area Temperature Hydration Local pH Tissue binding sites Drug-vehicle interactions

Developmental Alterations in Skin thickness

GA: 26 wkPNA: 1 day

GA: 26 wkPNA: 16 days

GA: 40 wkPNA: 1 day

Rutter. Clin Perinatol 1987;14:911

Impact of Enhanced Skin Permeability on Cutaneous Absorption

Neonatal Case Reports

Agent Resultant ADR

silver sulfadiazene cardiorespiratory arrest

topical steroids HPA suppressioncushingoid features

pentachlorophenol(laundry detergent)

diaphoresishepatomegaly

acidosis

boric acid(talcum powder)

death

Volume of Distribution

EC H2O IC H2O Protein Fat

0 20 40 60 80 100

Premature

Newborn

4 mo

12 mo

24 mo

36 mo

Adult

Age Dependent Changes in Body Composition

Impact of Changes in Extracellular Fluid on Drug Distribution

Siber et al. J Infect Dis 1975;132:637

0

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

Pea

k G

enta

mic

in C

once

ntra

tion

(mg/

L pe

r m

g/kg

dos

e)

Drug biotransformationDrug biotransformation

DrugDrugDrugDrugPhase IPhase I Phase IIPhase II

UGTsUGTsNATsNATs

SULTsSULTsMTsMTs

GSTsGSTs

MetaboliteMetabolite

CYPsCYPsFMOsFMOs

EsterasesEsterasesHydrolasesHydrolases

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

FMO3ADH1C

CYP2C9 UGT1A1

CYP1A2 SULT2A1

EPHX1

ADH1B EPHX2

CYP3A4 PON1

GSTMAOX

Hines, Pharmacol & Therap. 118:250-267, 2008

Human DME OntogenyHuman DME OntogenyD

ME

(p

mol/m

g p

rote

in)

0

10

20

30

40

EGA10-26 wks

EGA>26-40 wks

PNA0-6 mo

PNA>6 mo-18 yr

SULT1E1Class 1

SULT1A1Class 2

CYP2C9Class 3

Ontogeny of CYP2C19 Ontogeny of CYP2C19 In VitroIn Vitro

Koukouritaki Koukouritaki et al et al J Pharmacol Exp Ther 2004;308:965-974.J Pharmacol Exp Ther 2004;308:965-974.

EGA (Weeks)EGA (Weeks) PNA (Months)PNA (Months) PNA (Years)PNA (Years)

00 33 66 99 1212 1515 181866 1414 2222 3030 3838 11 22 33 44 55

4040

3030

2020

00

1010

00

1010

2020

3030

CY

P2C

19 P

rote

in (

pmol

/mg)

CY

P2C

19 P

rote

in (

pmol

/mg)

Ontogeny of CYP2C19 Ontogeny of CYP2C19 In VivoIn Vivo

Ward Ward et al et al Eur J Clin Pharmacol 2010;66:555-561Eur J Clin Pharmacol 2010;66:555-561

rr22 = 0.35 = 0.35

Postmenstrual AgePostmenstrual Age Postnatal AgePostnatal Age

APAP Biotransformation in HumansAPAP Biotransformation in Humans

APAP

APAP-G

NAPQI

APAP-S

Mercapturate

Ratio Gluc:SulfMean SE

Newborns N=4 0.340.08

3-9 yr N=7 0.750.10

12 yr N=4 1.610.21

Adults N=4 1.801.32

UGT1A6UGT1A9

SULT1A1

CYP3A4CYP3A4CYP1A2CYP1A2CYP2E1CYP2E1

Miller, et al. Clin. Pharmacol. Ther. 19:284-294, 1976

Impact of Developmental Alterations in Phase II Enzymes on Drug Metabolism: Acetaminophen

12610-365 days (n=7)

210term <10 days (n=5)

265Preterm 32-36 wk (n=10)

290Preterm <32 wk (n=10)

APAP t1/2 min (IV paracetamol)

Age

Allegaert, et al. Arch Dis Child Fetal Neonatal Ed. 2004;89:25-28

Term

Preterm (<2000gm)

Preterm (<1500 gm)

0

10

20

30

40

50

60

70

1-2 d 8-9 d 15-16 d

GF

R (

ml/m

in/1

.73m

2)

Postnatal Age

Developmental Alterations in Glomerular Filtration

Impact of Developmental Alterations in Renal Function on Drug Elimination

< 29 wk, <14 d

q72hr

< 29 wk, >14 d

q48hr

30-36 wk, <14 d

q48hr

30-36 wk, >14 d

q24hr

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 19.5-25

Saxen, et al. Clin Pharmacol Ther 1993;54:269

Intestinal EffluxP-gp, MRP2, MRP1,

OCT1, OATP3,NTCP

Biliary ExcretionP-gp, MRP3, MRP2, sPGP

Hepatic UptakeOATP2, OATP8, OATP-B, OCT1, NTCP,

OAT2, OAT3

Renal SecretionOAT1, OAT3, OCT1,

OCT2, OATP,P-gp, MRP1

Brain TransportP-gp, OAT3,

MRP1, MRP5,OATP1

Ritschel WA and Kearns GL. Handbook of Basic Pharmacokinetics, 7 th edition, 2009

Pediatric Clinical Pharmacology FactsPediatric Clinical Pharmacology Facts

Children are not small adultsChildren are not small adults different pharmacokineticsdifferent pharmacokinetics different pharmacodynamicsdifferent pharmacodynamics

Approximately 70% of all marketed Approximately 70% of all marketed drugs not suitably labeled for drugs not suitably labeled for pediatric usepediatric use

In some instances, pediatric In some instances, pediatric patients included in studies as an patients included in studies as an “afterthought”“afterthought”

The biggest issue remains The biggest issue remains determining the effective/safe determining the effective/safe dose for pediatricsdose for pediatrics

The In-silico Child…….

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

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?

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

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

CONCLUSIONS

TEAM WORK TEAM WORK TEAM WORK TEAM WORK TEAM WORK