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Presented at the November 17, 2003 meeting of the Clinical Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical Science by Gregory Kearns,

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Presentation on theme: "Presented at the November 17, 2003 meeting of the Clinical Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical Science by Gregory Kearns,"— Presentation transcript:

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 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 ?

4 Age-Dependent Changes in Body Composition

5 Ontogeny of Glomerular Filtration Preterm (<1500 g) Preterm (<2000 g) TermTerm Postnatal Age GFR (ml/min/1.73 m 2 ) From Ritschel WA and Kearns GL, 1998

6 Famotidine Disposition in Pediatrics Patient GroupT 1/2 CLCLrenal (hr)(L/hr/kg)(L/hr/kg) Children (n=12, 1.1-12.9 yr)3.20.70 0.45 Neonates (n=10, 936-3495 gm)10.90.13 0.09 Patient GroupT 1/2 CLCLrenal (hr)(L/hr/kg)(L/hr/kg) Children (n=12, 1.1-12.9 yr)3.20.70 0.45 Neonates (n=10, 936-3495 gm)10.90.13 0.09 Abbreviations: CL, total plasma clearance and CLrenal, renal clearance Data expressed as mean values from James et. al. (1998) Abbreviations: CL, total plasma clearance and CLrenal, renal clearance Data expressed as mean values from James et. al. (1998)

7 Age (days) Scaled Activity as a Fraction of Adult Values of Adult Values Pattern of Ontogeny for Selected Cytochromes P450 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 28-36 wks.36-42 wks.42-54 wks. 28-36 wks.36-42 wks.42-54 wks. (n = 17)(n = 13)(n = 5) (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.)

9 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)

10 APAP-G:APAP-S ratio over time 0.20.2 0.4 0.6 0.8 534216 G:S Ratio Age in months 9 Behm MO, et al. Clin Pharmacol Ther (abst.), Feb. 2003

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

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

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

14 The Remaining Challenges of Pediatric Drug 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

15 Pediatric Study Decision Tree Reasonable to assume (pediatrics vs adults)  similar disease progression  similar response to intervention Conduct PK studiesConduct PK studies Conduct safety/efficacy trials*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 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 concentration-response (C-R) in pediatrics and adults ? Conduct PK studies to achieve levels similar to adultsConduct PK studies to achieve levels similar to adults Conduct safety trialsConduct safety trials NO YES TO BOTH YES NO NO YES FDA Exposure-Response Guidance, April 2003

16 A Study of an Acid-Modifying Drug in Infants 1 to 12 Months of Age…… How would you (or most folks) approach it? How would you (or most folks) approach it? Select otherwise healthy infants who are being treated with acid modifying drugs 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 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 Use robust, minimal sampling techniques Assess pharmacologic effect of drug if possible Assess pharmacologic effect of drug if possible Design effect studies with target exposure-response data to drive dose selection Design effect studies with target exposure-response data to drive dose selection Assess pharmacologic effect, treatment effect and tolerability in an age- appropriate manner Assess pharmacologic effect, treatment effect and tolerability in an age- appropriate manner

17 A Study of an Acid Modifying Drug in Infants 1 to 12 Months of Age…… Past recommendations from the Agency*? Past recommendations from the Agency*? Use of primary disease endpoints to assess efficacy: Use of primary disease endpoints to assess efficacy: Obstructive apnea Esophageal erosion Secondary endpoints to assess effect Secondary endpoints to assess effect Intragastric/esophageal pH Esophageal impedance Single-dose and multiple-dose PK with sampling through 24 hours Single-dose and multiple-dose PK with sampling through 24 hours Study of 2-3 different fixed doses Study of 2-3 different fixed doses PK & safety in neonatal and p53 knockout mice PK & safety in neonatal and p53 knockout mice Subject follow-up through adolescence Subject follow-up through adolescence Denotes that recommendations continueDenotes 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 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 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) 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” 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 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) 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 Conduct PK studiesConduct PK studies Conduct safety/efficacy trials*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 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 concentration-response (C-R) in pediatrics and adults ? Conduct PK studies to achieve levels similar to adultsConduct PK studies to achieve levels similar to adults Conduct safety trialsConduct safety trials NO YES TO BOTH YES NO NO YES FDA Exposure-Response Guidance, April 2003

20 Challenges to Extrapolation in Pediatric Drug Development The pediatric disease process… The pediatric disease process… Is rarely substantially similar to adults with regard to:Is rarely substantially similar to adults with regard to: Onset Onset Progression Progression Expression of symptoms Expression of symptoms Disease- environment- treatment interface Disease- environment- treatment interface The concentration- effect relationship between children and adults is often similar.. The concentration- effect relationship between children and adults is often similar.. Receptor expression Drug-receptor interaction pertaining to: Time Concentration dependence

21 Reasonable to assume (pediatrics vs adults)  similar DRUG EFFECT (MOA)  similar CONCENTRATION-EFFECT  similar EFFECTOR RESPONSE Conduct PK studiesConduct PK studies Conduct safety/efficacy trials*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 MEASUREMENTConduct 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 doseConduct PK studies to achieve target concentrations based on C-R and to determine pediatric dose Conduct TOLERABILITY trialsConduct 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 doseConduct PK studies to achieve levels similar to adults and determine proper pediatric dose Conduct TOLERABILITY trialsConduct TOLERABILITY trials NO YES TO 2 or MORE YES NO NO YES Adaptation of FDA Exposure-Response Guidance, Nov. 2003

22 The Holy Grail of Extrapolation…… Forget about the disease being “substantially similar” Forget about the disease being “substantially similar” Focus on the drug response being “substantially similar” Focus on the drug response being “substantially similar” Abandon the “morbid- mortal” outcome Abandon the “morbid- mortal” outcome Base assessment of drug effect and tolerability on similar exposures 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 MANDATE USE OF A SUITABLE PEDIATRIC DECISION TREE THAT IS DRIVEN BY EXPOSURE- RESPONSE GUIDANCE

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

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