Presented at the November 17, 2003

meeting of theClinical Pharmacology Subcommittee

of theAdvisory Committee for Pharmaceutical Science

byGregory Kearns, Pharm.D, Ph.D.

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

Dr. Abraham Jacobi, 1889Dr. Abraham Jacobi, 1889

The Developmental ContinuumThe Developmental Continuum

Fetus

Newborn

Infant

Preschooler

School-age

Adolescent

Adult

Fetus

Newborn

Infant

Preschooler

School-age

Adolescent

Adult

Weight doubles by 5 months; triples by 1 year Body surface area doubles by 1 year Caloric expenditures increase 3- to 4-fold by 1

year

Adolescence: transition to adulthood Changes incomprehensible to most adults

Weight doubles by 5 months; triples by 1 year Body surface area doubles by 1 year Caloric expenditures increase 3- to 4-fold by 1

year

Adolescence: transition to adulthood Changes incomprehensible to most adults

?

0

20

40

60

80

100

Birth 3

mo.

6

mo.

9

mo.

1 yr. 5 yr. 10

yr.

20

yr.

40

yr.

TBW

ECW

Body Fat

0

20

40

60

80

100

Birth 3

mo.

6

mo.

9

mo.

1 yr. 5 yr. 10

yr.

20

yr.

40

yr.

TBW

ECW

Body Fat

Age-Dependent Changes in Body CompositionAge-Dependent Changes in Body Composition

1-2 d8-9 d

15-16 d

0

10

20

30

40

50

60

70

Ontogeny of Glomerular FiltrationOntogeny of Glomerular FiltrationOntogeny of Glomerular FiltrationOntogeny of Glomerular Filtration

Preterm (<1500 g)Preterm (<1500 g)Preterm (<1500 g)Preterm (<1500 g)

Preterm (<2000 g)Preterm (<2000 g)Preterm (<2000 g)Preterm (<2000 g)TermTermTermTerm

Postnatal AgePostnatal AgePostnatal AgePostnatal Age

GF

R (

ml/

min

/1.7

3 m

GF

R (

ml/

min

/1.7

3 m

22 ))G

FR

(m

l/m

in/1

.73

mG

FR

(m

l/m

in/1

.73

m22 ))

From Ritschel WA and Kearns GL, 1998From Ritschel WA and Kearns GL, 1998

Famotidine Disposition in PediatricsFamotidine Disposition in PediatricsFamotidine Disposition in PediatricsFamotidine Disposition in Pediatrics

Patient Group T1/2 CL CLrenal(hr) (L/hr/kg) (L/hr/kg)

Children (n=12, 1.1-12.9 yr) 3.2 0.70 0.45

Neonates(n=10, 936-3495 gm) 10.9 0.13 0.09

Patient Group T1/2 CL CLrenal(hr) (L/hr/kg) (L/hr/kg)

Children (n=12, 1.1-12.9 yr) 3.2 0.70 0.45

Neonates(n=10, 936-3495 gm) 10.9 0.13 0.09

Abbreviations: CL, total plasma clearance and CLrenal, renal clearanceAbbreviations: CL, total plasma clearance and CLrenal, renal clearanceData expressed as mean values from James et. al. (1998)Data expressed as mean values from James et. al. (1998)Abbreviations: CL, total plasma clearance and CLrenal, renal clearanceAbbreviations: CL, total plasma clearance and CLrenal, renal clearanceData expressed as mean values from James et. al. (1998)Data expressed as mean values from James et. al. (1998)

0

0.1

0.2

0.3

0.4

0.5

0.6

1 2 4 20 60 160

CYP1A2

CYP2C9

CYP2D6

CYP3A4

Age (days)Age (days)

Sca

led

Act

ivit

y as

a F

ract

ion

Sca

led

Act

ivit

y as

a F

ract

ion

of

Ad

ult

Val

ues

of

Ad

ult

Val

ues

Pattern of Ontogeny for Selected Cytochromes P450Pattern of Ontogeny for Selected Cytochromes P450

from Alcorn and McNamara, Clin. Pharmacokinet., 2003;41:1077-94

Single-Dose (0.2 mg/kg) Pharmacokinetics Single-Dose (0.2 mg/kg) Pharmacokinetics of Cisapride in Neonates and Young Infantsof Cisapride in Neonates and Young Infants

28-36 wks.28-36 wks. 36-42 wks.36-42 wks. 42-54 wks.42-54 wks. (n = 17)(n = 17) (n = 13)(n = 13) (n = 5)(n = 5)

Postconceptional AgePostconceptional Age

Cmax (ng/ml)Cmax (ng/ml) 30.0(17.5) 30.0(17.5) 23.3(11.7)23.3(11.7) 44.5(19.5)44.5(19.5)Tmax (hr)Tmax (hr) 5.0(2.6)5.0(2.6) 4.3(3.3)4.3(3.3) 2.2(1.1)2.2(1.1)T1/2 (hr)T1/2 (hr) 11.6(3.0)11.6(3.0) 11.5(3.0)11.5(3.0) 4.8(3.0)4.8(3.0)AUC (ng/ml*hr)AUC (ng/ml*hr) 568(257) 568(257) 362(198)362(198) 364(249)364(249)VDss/F (L/kg)VDss/F (L/kg) 7.4(4.7) 7.4(4.7) 12.7(9.1)12.7(9.1) 4.1(1.5)4.1(1.5)Cl/F (L/hr/kg)Cl/F (L/hr/kg) 0.45(0.26)0.45(0.26) 0.75(0.46)0.75(0.46) 0.85(0.69)0.85(0.69)

Kearns GL, et al. Kearns GL, et al. Clin Pharmacol TherClin Pharmacol Ther, October 2003, October 2003-Data expressed as mean (S.D.)-Data expressed as mean (S.D.)

Age-Related Changes in Intestinal Age-Related Changes in Intestinal CYP3A4 Activity (villin-corrected)CYP3A4 Activity (villin-corrected)

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Fetus Neonate >3 mo - 2yr

>2-5yr >5-12yr >12yr

6OHT

0

0.01

0.02

0.03

0.04

0.05

0.06

0.07

Fetus Neonate >3 mo - 2yr

>2-5yr >5-12yr >12yr

6OHT

Johnson TN, et al. Br J Clin Pharmacol 2001;51:451-460

6OH

T (

nmol

/mg

prot

ein

/ min

)

APAP-G:APAP-S ratio over timeAPAP-G:APAP-S ratio over timeAPAP-G:APAP-S ratio over timeAPAP-G:APAP-S ratio over time

0.2

0.4

0.6

0.8

53 421 6

G:S

Rat

io

Age in months9

Behm MO, et al. Clin Pharmacol Ther (abst.), Feb. 2003Behm MO, et al. Clin Pharmacol Ther (abst.), Feb. 2003

Kearns GL, et al. Clin Pharmacol Ther, Nov. 2003

Linezolid Plasma Clearance Association with PNALinezolid Plasma Clearance Association with PNA

Pediatric Clinical Pharmacology FactsPediatric Clinical Pharmacology Facts

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

Approximately 80% of all marketed drugs not Approximately 80% of all marketed drugs not suitably labeled for pediatric usesuitably labeled for pediatric use

With rare exception, pediatric patients included With rare exception, pediatric patients included in studies as an “afterthought”in studies as an “afterthought”

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

Previous Challenges to Pediatric Drug Previous Challenges to Pediatric Drug Development are No Longer InsurmountableDevelopment are No Longer Insurmountable

Previous Challenges to Pediatric Drug Previous Challenges to Pediatric Drug Development are No Longer InsurmountableDevelopment are No Longer Insurmountable

AnalyticalAnalytical PK/PD approachesPK/PD approaches ScientificScientific LogisticalLogistical LegalLegal EthicalEthical ProgrammaticProgrammatic RegulatoryRegulatory

The Remaining Challenges of Pediatric The Remaining Challenges of Pediatric Drug DevelopmentDrug Development

Relevant extrapolation of:Relevant extrapolation of:• Adult dataAdult data• Animal dataAnimal data

Study designs that are:Study designs that are:• Optimal and appropriate for ageOptimal and appropriate for age• Scientifically robustScientifically robust• Synergized by addition of relevant scienceSynergized by addition of relevant science• Capable of critically addressing effectCapable of critically addressing effect

Dosing approaches that:Dosing approaches that:• Control exposure (and thus, response)Control exposure (and thus, response)• Are verifiableAre verifiable• Are age appropriateAre age appropriate

Pediatric Study Decision TreePediatric Study Decision Tree

Reasonable to assume (pediatrics vs adults)Reasonable to assume (pediatrics vs adults) similar disease progressionsimilar disease progression similar response to interventionsimilar response to intervention

•Conduct PK studiesConduct PK studies

•Conduct safety/efficacy trials*Conduct safety/efficacy trials*

Is there a PD measurement**Is there a PD measurement**

that can be used to predictthat can be used to predict

efficacy ?efficacy ?

•Conduct PK/PD studies to get C-R for PD MEASUREMENTConduct PK/PD studies to get C-R for PD MEASUREMENT

•Conduct PK studies to achieve target concentrations based on C-RConduct PK studies to achieve target concentrations based on C-R

•Conduct safety trialsConduct safety trials

Reasonable to assume similar Reasonable to assume similar concentration-response (C-R) in concentration-response (C-R) in pediatrics and adults ?pediatrics and adults ?

•Conduct PK studies to achieve levels Conduct PK studies to achieve levels similar to adults similar to adults

•Conduct safety trialsConduct safety trials

NO NO YES TO BOTH YES TO BOTH

YESYES

NONO NONOYES YES

FDA Exposure-Response Guidance, April 2003FDA Exposure-Response Guidance, April 2003

A Study of an Acid-Modifying Drug in Infants 1 to A Study of an Acid-Modifying Drug in Infants 1 to 12 Months of Age……12 Months of Age……

How would you How would you (or most folks) (or most folks) approach it?approach it?

Select otherwise healthy infants Select otherwise healthy infants who are being treated with acid who are being treated with acid modifying drugsmodifying drugs

Use known PK / PD properties of Use known PK / PD properties of drug + evidence for ontogeny drug + evidence for ontogeny effect on either DME (or effect on either DME (or clearance pathway) and/or Pcol clearance pathway) and/or Pcol effect to design studyeffect to design study

Use robust, minimal sampling Use robust, minimal sampling techniquestechniques

Assess pharmacologic effect of Assess pharmacologic effect of drug if possibledrug if possible

Design effect studies with Design effect studies with target exposure-response data target exposure-response data to drive dose selectionto drive dose selection

Assess pharmacologic effect, Assess pharmacologic effect, treatment effect and tolerability treatment effect and tolerability in an age-appropriate mannerin an age-appropriate manner

A Study of an Acid Modifying Drug in Infants A Study of an Acid Modifying Drug in Infants 1 to 12 Months of Age……1 to 12 Months of Age……

Past Past recommendations recommendations from the Agency*?from the Agency*?

Use of primary disease Use of primary disease endpoints to assess efficacy:endpoints to assess efficacy:• Obstructive apneaObstructive apnea• Esophageal erosionEsophageal erosion

Secondary endpoints to Secondary endpoints to assess effectassess effect• Intragastric/esophageal pH Intragastric/esophageal pH • Esophageal impedanceEsophageal impedance

Single-dose and multiple-dose Single-dose and multiple-dose PK with sampling through 24 PK with sampling through 24 hourshours

Study of 2-3 different fixed Study of 2-3 different fixed dosesdoses

PK & safety in neonatal and PK & safety in neonatal and p53 knockout micep53 knockout mice

Subject follow-up through Subject follow-up through adolescence adolescence

•Denotes that recommendations continueDenotes that recommendations continueto be an evolving “work in progress”to be an evolving “work in progress”

The approach now becomes an impediment The approach now becomes an impediment consequent to slippage in the regulations and their consequent to slippage in the regulations and their

interpretationinterpretation

Exclusivity provisions of BPCA enable labeling only if the “disease Exclusivity provisions of BPCA enable labeling only if the “disease process is substantially similar” between pediatric patients and process is substantially similar” between pediatric patients and adultsadults

A belief (by some) that dosing and safety information is not wholly A belief (by some) that dosing and safety information is not wholly sufficient for exclusivity and pediatric labeling but rather, phase III sufficient for exclusivity and pediatric labeling but rather, phase III studies to prove efficacy for same or new indication are neededstudies to prove efficacy for same or new indication are needed

Granting of exclusivity increasingly viewed as a privilege and as Granting of exclusivity increasingly viewed as a privilege and as such, it is being carefully managed (eg., appx. 25% of issued such, it is being carefully managed (eg., appx. 25% of issued written requests)written requests)

Differential interpretation of the regulations by the “Tower of Differential interpretation of the regulations by the “Tower of Review Divisions”Review Divisions”

Problems and in some instances, apparent failures with regard to Problems and in some instances, apparent failures with regard to effective / seamless integration of Pediatric Division and Clinical effective / seamless integration of Pediatric Division and Clinical Pharmacology with Review DivisionsPharmacology with Review Divisions

The entire pediatric initiative largely remains as an unfunded The entire pediatric initiative largely remains as an unfunded mandate for the Agency (including BPCA and off-patent initiative)mandate for the Agency (including BPCA and off-patent initiative)

Pediatric Study Decision TreePediatric Study Decision Tree

Reasonable to assume (pediatrics vs adults)Reasonable to assume (pediatrics vs adults) similar disease progressionsimilar disease progression similar response to interventionsimilar response to intervention

•Conduct PK studiesConduct PK studies

•Conduct safety/efficacy trials*Conduct safety/efficacy trials*

Is there a PD measurement**Is there a PD measurement**

that can be used to predictthat can be used to predict

efficacy ?efficacy ?

•Conduct PK/PD studies to get C-R for PD MEASUREMENTConduct PK/PD studies to get C-R for PD MEASUREMENT

•Conduct PK studies to achieve target concentrations based on C-RConduct PK studies to achieve target concentrations based on C-R

•Conduct safety trialsConduct safety trials

Reasonable to assume similar Reasonable to assume similar concentration-response (C-R) in concentration-response (C-R) in pediatrics and adults ?pediatrics and adults ?

•Conduct PK studies to achieve levels Conduct PK studies to achieve levels similar to adults similar to adults

•Conduct safety trialsConduct safety trials

NO NO YES TO BOTH YES TO BOTH

YESYES

NONO NONOYES YES

FDA Exposure-Response Guidance, April 2003FDA Exposure-Response Guidance, April 2003

Challenges to Extrapolation in Pediatric Challenges to Extrapolation in Pediatric Drug DevelopmentDrug Development

The pediatric The pediatric disease process…disease process…• Is rarely Is rarely

substantially similar substantially similar to adults with regard to adults with regard to:to:

OnsetOnset ProgressionProgression Expression of Expression of

symptomssymptoms Disease-environment-Disease-environment-

treatment interfacetreatment interface

The concentration-The concentration-effect relationship effect relationship between children and between children and adults is often similar..adults is often similar..• Receptor expressionReceptor expression• Drug-receptor Drug-receptor

interaction pertaining interaction pertaining to:to:

TimeTime Concentration Concentration

dependencedependence

Reasonable to assume (pediatrics vs adults)Reasonable to assume (pediatrics vs adults) similar similar DRUG EFFECT (MOA)DRUG EFFECT (MOA) similar similar CONCENTRATION-EFFECTCONCENTRATION-EFFECT similar EFFECTOR RESPONSEsimilar EFFECTOR RESPONSE

•Conduct PK studiesConduct PK studies

•Conduct safety/efficacy trials*Conduct safety/efficacy trials*

Is there a PD measurement**Is there a PD measurement**

that can be used to predictthat can be used to predict

drug effectdrug effect ? ?

•Conduct PK/PD studies to get C-R for PD MEASUREMENTConduct PK/PD studies to get C-R for PD MEASUREMENT

•Conduct PK studies to achieve target concentrations based on C-R Conduct PK studies to achieve target concentrations based on C-R and to determine pediatric doseand to determine pediatric dose

•Conduct Conduct TOLERABILITYTOLERABILITY trials trials

Reasonable to assume similar Reasonable to assume similar concentration-response (C-R) in concentration-response (C-R) in pediatrics and adults ?pediatrics and adults ?

•Conduct PK studies to achieve levels Conduct PK studies to achieve levels similar to adults similar to adults and determine and determine proper pediatric doseproper pediatric dose

•Conduct Conduct TOLERABILITYTOLERABILITY trials trials

NO NO YES TO YES TO 2 or MORE2 or MORE

YESYES

NONO NONOYES YES

Adaptation of FDA Exposure-Response Guidance, Nov. 2003Adaptation of FDA Exposure-Response Guidance, Nov. 2003

The Holy Grail of Extrapolation……The Holy Grail of Extrapolation……

Forget about the disease Forget about the disease being “substantially similar”being “substantially similar”

Focus on the drug response Focus on the drug response being “substantially similar”being “substantially similar”

Abandon the “morbid-Abandon the “morbid-mortal” outcomemortal” outcome

Base assessment of drug Base assessment of drug effect and tolerability on effect and tolerability on similar exposuressimilar exposures

MANDATE USE OF A MANDATE USE OF A SUITABLE PEDIATRIC SUITABLE PEDIATRIC DECISION TREE THAT IS DECISION TREE THAT IS DRIVEN BY EXPOSURE-DRIVEN BY EXPOSURE-RESPONSE GUIDANCERESPONSE GUIDANCE

To improve the current status of pediatric To improve the current status of pediatric drug development, simply adhere to the drug development, simply adhere to the

fundamental principles of Clinical fundamental principles of Clinical Pharmacology and think about things like Pharmacology and think about things like

Albert did……Albert did……

“ “ The significant problems of The significant problems of lifelifecan not be solved at the level can not be solved at the level ofofthinking that created them.”thinking that created them.”Albert Einstein