# Presentation: 810565

## Presented at the 

**November 17, 2003**
**meeting of the**
**Clinical Pharmacology Subcommittee **
**of the**
**Advisory Committee for Pharmaceutical Science**
**by**
**Gregory Kearns, Pharm.D, Ph.D.**

## “ 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...”

- “ 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

## The Developmental Continuum

- 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

**?**

## Age-Dependent Changes in Body Composition

## Ontogeny of Glomerular Filtration

**Preterm (<1500 g)**

**Preterm (<2000 g)**

**Term**

**Postnatal Age**

**GFR (ml/min/1.73 m****2****)**

*From Ritschel WA and Kearns GL, 1998*

## Famotidine Disposition in Pediatrics

**Patient Group****	****T****1/2****	****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 clearance***
***Data expressed as mean values from James et. al. (1998)***

## Pattern of Ontogeny for Selected Cytochromes P450

**Age (days)**

**Scaled Activity as a Fraction**
** ****of Adult Values**

**Pattern of Ontogeny for Selected Cytochromes P450**

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

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

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

**Postconceptional Age**

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

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

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

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

- 6OHT  (nmol/mg protein / min)

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

**0****.****2**

**0.4**

**0.6**

**0.8**

**5**

**3**

**4**

**2**

**1**

**6**

**G:S Ratio**

**Age in months**

**9**

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

## Linezolid Plasma Clearance Association with PNA

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

## Pediatric Clinical Pharmacology Facts

- Children are not small adults
- different pharmacokinetics
- different pharmacodynamics
- Approximately 80% of all marketed drugs not suitably labeled for pediatric use
- With rare exception, pediatric patients included in studies as an “afterthought”
- The biggest issue remains determining the effective/safe dose for pediatrics

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

- Analytical
- PK/PD approaches
- Scientific
- Logistical
- Legal
- Ethical
- Programmatic
- Regulatory

## The Remaining Challenges of Pediatric Drug Development

- Relevant extrapolation of:
- Adult data
- Animal data
- Study designs that are:
- Optimal and appropriate for age
- Scientifically robust
- Synergized by addition of relevant science
- Capable of critically addressing effect
- Dosing approaches that:
- Control exposure (and thus, response)
- Are verifiable
- Are age appropriate

## Pediatric Study Decision Tree

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

- Conduct PK studies
- Conduct safety/efficacy trials*

- Is there a PD measurement**
- that can be used to predict
- efficacy ?

- Conduct PK/PD studies to get C-R for PD MEASUREMENT
- Conduct PK studies to achieve target concentrations based on C-R
- Conduct safety trials

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

- Conduct PK studies to achieve levels     similar to adults
- Conduct safety trials

- NO

- YES TO BOTH

- YES

- NO

- NO

- YES

- FDA Exposure-Response Guidance, April 2003

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

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

- Select otherwise healthy infants who are being treated with acid modifying drugs
- Use known PK / PD properties of drug + evidence for ontogeny effect on either DME (or clearance pathway) and/or Pcol effect to design study
- Use robust, minimal sampling techniques
- Assess pharmacologic effect of drug if possible
- Design effect studies with target exposure-response data to drive dose selection
- Assess pharmacologic effect, treatment effect and tolerability in an age-appropriate manner

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

- Past recommendations from the Agency*?

- Use of primary disease endpoints to assess efficacy:
- Obstructive apnea
- Esophageal erosion
- Secondary endpoints to assess effect
- Intragastric/esophageal pH
- Esophageal impedance
- Single-dose and multiple-dose PK with sampling through 24 hours
- Study of 2-3 different fixed doses
- PK & safety in neonatal and p53 knockout mice
- Subject follow-up through adolescence

*Denotes that recommendations continue*
*to be an evolving “work in progress”*

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

- Exclusivity provisions of BPCA enable labeling only if the “disease process is substantially similar” between pediatric patients and adults
- A belief (by some) that dosing and safety information is not wholly sufficient for exclusivity and pediatric labeling but rather, phase III studies to prove efficacy for same or new indication are needed
- Granting of exclusivity increasingly viewed as a privilege and as such, it is being carefully managed (eg., appx. 25% of issued written requests)
- Differential interpretation of the regulations by the “Tower of Review Divisions”
- Problems and in some instances, apparent failures with regard to effective / seamless integration of Pediatric Division and Clinical Pharmacology with Review Divisions
- The entire pediatric initiative largely remains as an unfunded mandate for the Agency (including BPCA and off-patent initiative)

## Pediatric Study Decision Tree

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

- Conduct PK studies
- Conduct safety/efficacy trials*

- Is there a PD measurement**
- that can be used to predict
- efficacy ?

- Conduct PK/PD studies to get C-R for PD MEASUREMENT
- Conduct PK studies to achieve target concentrations based on C-R
- Conduct safety trials

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

- Conduct PK studies to achieve levels     similar to adults
- Conduct safety trials

- NO

- YES TO BOTH

- YES

- NO

- NO

- YES

- FDA Exposure-Response Guidance, April 2003

## Challenges to Extrapolation in Pediatric Drug Development

- The pediatric disease process...
- Is rarely substantially similar to adults with regard to:
- Onset
- Progression
- Expression of symptoms
- Disease-environment-treatment interface

- The concentration-effect relationship between children and adults is often similar..
- Receptor expression
- Drug-receptor interaction pertaining to:
- Time
- Concentration dependence

## Reasonable to assume (pediatrics vs adults)

-  similar DRUG EFFECT (MOA)
-  similar CONCENTRATION-EFFECT
-  similar EFFECTOR RESPONSE

- Conduct PK studies
- Conduct safety/efficacy trials*

- Is there a PD measurement**
- that can be used to predict
- drug effect ?

- Conduct PK/PD studies to get C-R for PD MEASUREMENT
- Conduct PK studies to achieve target concentrations based on C-R and to determine pediatric dose
- Conduct TOLERABILITY trials

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

- Conduct PK studies to achieve levels     similar to adults and determine proper pediatric dose
- Conduct TOLERABILITY trials

- NO

- YES TO 2 or MORE

- YES

- NO

- NO

- YES

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

## The Holy Grail of Extrapolation......

- Forget about the disease being “substantially similar”
- Focus on the drug response being “substantially similar”
- Abandon the “morbid-mortal” outcome
- Base assessment of drug effect and  tolerability on _similar exposures_
- _MANDATE USE OF A SUITABLE PEDIATRIC DECISION TREE THAT IS DRIVEN BY EXPOSURE-RESPONSE GUIDANCE_

## To improve the current status of pediatric drug development, simply adhere to the fundamental principles of Clinical Pharmacology  and think about things like Albert did......