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Presented at the November 17, 2003 meeting of the Clinical Pharmacology Subcommittee of the Advisory Committee for Pha

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.

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Presented at the November 17, 2003 meeting of the Clinical Pharmacology Subcommittee of the Advisory Committee for Pha

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  1. 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.

  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. 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 ?

  4. Age-Dependent Changes in Body Composition

  5. Ontogeny of Glomerular Filtration GFR (ml/min/1.73 m2) Term Preterm (<2000 g) Preterm (<1500 g) Postnatal Age From Ritschel WA and Kearns GL, 1998

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

  7. Pattern of Ontogeny for Selected Cytochromes P450 Scaled Activity as a Fraction of Adult Values Age (days) from Alcorn and McNamara, Clin. Pharmacokinet., 2003;41:1077-94

  8. Single-Dose (0.2 mg/kg) Pharmacokinetics of Cisapride in Neonates and Young Infants Postconceptional Age 28-36 wks. 36-42 wks. 42-54 wks. (n = 17) (n = 13) (n = 5) 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.)

  9. Age-Related Changes in Intestinal CYP3A4 Activity (villin-corrected) 6OHT (nmol/mg protein / min) Johnson TN, et al. Br J Clin Pharmacol 2001;51:451-460

  10. APAP-G:APAP-S ratio over time 0.8 0.6 G:S Ratio 0.4 0.2 1 2 3 4 5 6 9 Age in months Behm MO, et al. Clin Pharmacol Ther (abst.), Feb. 2003

  11. Linezolid Plasma Clearance Association with PNA Kearns GL, et al. Clin Pharmacol Ther, Nov. 2003

  12. 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

  13. Previous Challenges to Pediatric Drug Development are No Longer Insurmountable • Analytical • PK/PD approaches • Scientific • Logistical • Legal • Ethical • Programmatic • Regulatory

  14. 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

  15. Pediatric Study Decision Tree • Reasonable to assume (pediatrics vs adults) • similar disease progression • similar response to intervention NO YES TO BOTH • Conduct PK studies • Conduct safety/efficacy trials* Reasonable to assume similar concentration-response (C-R) in pediatrics and adults ? NO NO YES Is there a PD measurement** that can be used to predict efficacy ? • Conduct PK studies to achieve levels similar to adults • Conduct safety trials YES • 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 FDA Exposure-Response Guidance, April 2003

  16. 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……

  17. 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 A Study of an Acid Modifying Drug in Infants 1 to 12 Months of Age…… • Denotes that recommendations continue • to be an evolving “work in progress”

  18. 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)

  19. Pediatric Study Decision Tree • Reasonable to assume (pediatrics vs adults) • similar disease progression • similar response to intervention NO YES TO BOTH • Conduct PK studies • Conduct safety/efficacy trials* Reasonable to assume similar concentration-response (C-R) in pediatrics and adults ? NO NO YES Is there a PD measurement** that can be used to predict efficacy ? • Conduct PK studies to achieve levels similar to adults • Conduct safety trials YES • 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 FDA Exposure-Response Guidance, April 2003

  20. 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 Challenges to Extrapolation in Pediatric Drug Development

  21. Reasonable to assume (pediatrics vs adults) • similar DRUG EFFECT (MOA) • similar CONCENTRATION-EFFECT • similar EFFECTOR RESPONSE NO YES TO 2 or MORE • Conduct PK studies • Conduct safety/efficacy trials* Reasonable to assume similar concentration-response (C-R) in pediatrics and adults ? NO NO YES Is there a PD measurement** that can be used to predict drug effect ? • Conduct PK studies to achieve levels similar to adults and determine proper pediatric dose • Conduct TOLERABILITY trials YES • 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 Adaptation of FDA Exposure-Response Guidance, Nov. 2003

  22. 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

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

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