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Clinical Pharmacology Perspectives of Pediatric Dosing of Over-The-Counter (OTC) Cough and Cold Medications

Clinical Pharmacology Perspectives of Pediatric Dosing of Over-The-Counter (OTC) Cough and Cold Medications. Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee Silver Spring, Maryland October 18-19, 2007 Partha Roy, Ph.D.

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Clinical Pharmacology Perspectives of Pediatric Dosing of Over-The-Counter (OTC) Cough and Cold Medications

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  1. Clinical Pharmacology Perspectives of Pediatric Dosing of Over-The-Counter (OTC) Cough and Cold Medications Joint Meeting of the Nonprescription Drugs Advisory Committee and the Pediatric Advisory Committee Silver Spring, Maryland October 18-19, 2007 Partha Roy, Ph.D. Senior Clinical Pharmacologist Office of Clinical Pharmacology Office of Translational Sciences Center for Drug Evaluation and Research

  2. Outline • Issues raised in citizens petition • Ontogeny of renal and hepatic (metabolic) clearance mechanisms with age • Available pediatric PK data for OTC cough and cold drugs • Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution • Pediatric drug development: FDA’s current approach • Summary

  3. Citizen Petition • Raised significant concerns about the safety and efficacy of cough and cold medications in children 6 years and younger • Requested FDA to re-label these products to state that these products should not be used for the treatment of cough and cold in children under 6 years of age

  4. Basis for the petition • Reports of deaths and serious adverse events in which drugs commonly found in OTC cough and cold preparations were detected at very high concentrations mostly in infants and toddlers • The absence of specific dose and dosing interval information on the label for children under the age of 2 years constitutes a safety hazard in an age range highly vulnerable to overdose

  5. Outline • Issues raised in citizen’s petition • Ontogeny of renal and hepatic (metabolic pathways) functions with age • Available PK data for OTC cough and cold drugs • Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution • Pediatric drug development: FDA’s current approach • Summary

  6. Clearance pathways

  7. Ontogeny of clearance mechanisms: Renal Clearance (e.g. Pseudoephedrine) Glomerular Filtration • Renal maturation complete by 2 years of life Active Secretion Renal Blood flow RFP: Renal Function Parameter 2 years Hayton WL (2002) AAPS PharmSci 2 (1) article 3 (http://www.aapspharmsci.org)

  8. Ontogeny of clearance mechanisms: Hepatic Clearance (Dextromethorphan as an example)

  9. Impact of CYP2D6 polymorphism on drug exposure: Dextromethorphan Dextromethorphan (DM) PK in adults * 5-10% of Caucasians, 1-3% of Asians EM: extensive metabolizers PM: poor metabolizers Adopted from Blake MJ (2007) Clin. Pharmacol. Ther. 2007, 81, 510-516

  10. Ontogeny of CYP2D6 in the 1st year of life: Dextromethorphan (DM) / Dextrorphan (DX) urinary ratio as probe • No apparent age-related differences in CYP2D6 activity from 2 wks to 1 y of age • Large inter-individual variability ~ CYP2D6 genetic polymorphism Adopted from Blake MJ (2007) Clin. Pharmacol. Ther. 2007, 81, 510-516

  11. Ontogeny of CYP3A4: Midazolam as a probe • CYP3A4: gradual increase after birth acquiring 3/4th of adult activity by 2 y • Midazolam clearance in 2-15y > adults de Wilt et al. (1999) Clin. Pharmacokinet 37: 485-505

  12. Additional factors impacting drug exposure:Limited to lack of information • Ontogeny of other CYPs: 1A, 2B6, 2C, 2D6, 3A5, 2E1 • Ontogeny of Phase II enzymes (e.g. UGT) • Ontogeny of drug transporters • Effect of diet (breast feeding vs. formula feeding) on the ontogeny of drug metabolizing enzymes • Effect of pH: Gastric (absorption) and urinary (elimination)

  13. Summary of development of clearance pathways • Renal: • Renal maturation complete by 2 years • Metabolic: • Each drug metabolizing enzymes (DMEs) demonstrate an independent rate and pattern of maturation • Genetic polymorphism of DMEs impacts drug exposure in children • Large inter-individual variability in metabolic clearance in children

  14. Outline • Issues raised in citizen’s petition • Ontogeny of renal and hepatic (metabolic pathways) functions with age • Available PK data for OTC cough and cold drugs • Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution • Pediatric drug development: FDA’s current approach • Summary

  15. OTC Monograph Dosing in Children:Current Practice • Extrapolated from dosing in adults • Wide margin of safety • Based on age: convenient • Stratification mimics body weight * Range ** Professional labeling available

  16. Mean (CV%) Pseudoephedrine single dose PK in adults and children(Cross-study comparisons) • Systemic exposure in 2-11y children NMT adults • No PK data in children less than 2 years of age Note: Data obtained from Clinical Pharmacology Reviews of NDA 21-373 (Children’s Advil Cold Suspension) and NDA 21-374 (Advil Cold Sinus Liquigels)

  17. Mean (CV%) Chlorpheniramine single dose PK in adults and children(Cross-study comparisons) • Systemic exposure in 6-11y children NMT adults • No PK data in children less than 6 years of age Note: Data obtained from Clinical Pharmacology Reviews of NDA 21-587 (Children’s Advil Allergy Sinus Suspension)

  18. Mean Brompheniramine single dose PK in adults and children(Cross-study comparisons) • Systemic exposure in 6-11y children NMT adults • No PK data in children less than 6 years of age Adopted from Simons et al. (1999) J Allergy Clin. Immunol. 103: 223-26

  19. Focus on Clearance (CL/F)

  20. Outline • Issues raised in citizen’s petition • Ontogeny of renal and hepatic (metabolic pathways) functions with age • Available PK data for OTC cough and cold drugs • Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution • Pediatric drug development: FDA’s current thinking • Summary

  21. C:P ratio (measure of post-mortem redistribution) for OTC cough and cold drugs Factors influencing post-mortem drug redistribution • site & timing of post-mortem blood collection • type of biological matrix • sample processing • physicochemical characteristics of the drug: pka, volume of distribution * C:P ratio = heart blood : peripheral blood ratio Reference: Leikin JB and Watson WA. (2003) Clinical Toxicology, 41, 47-56.

  22. Outline • Issues raised in citizen’s petition • Ontogeny of renal and hepatic (metabolic pathways) functions with age • Available PK data for OTC cough and cold drugs • Addressing the high concentrations noted in post-mortem reports: post-mortem drug re-distribution • Pediatric drug development: FDA’s current approach • Summary

  23. FDA’s Current Approach:Objectives of Pediatric PK studies • Guidance for Industry: E11 Clinical Investigation of Medicinal Products in the Pediatric Population states the following: …..“Pharmacokinetic studies generally should be performed to support formulation development and determine pharmacokinetic parameters in different age groups to support dosing recommendation” • Guidance for Industry: General Considerations for Pediatric Pharmacokinetic Studies for Drugs and Biological Products states the following: ….. “In general, pharmacokinetic studies in the pediatric population should determine how the dosage regimen in the pediatric population should be adjusted to achieve approximately the same level of systemic exposure that is safe and effective in adults”

  24. FDA’s Current ApproachBridging efficacy data in an adult population to a pediatric population Reference: FDA’s Guidance for Industry (2003), Exposure-Response Relationships — Study Design, Data Analysis, and Regulatory Applications

  25. Key Considerations for Pediatric PK studies • Monotherapy: single ingredient evaluation • Single and multiple dose evaluation • Adequate number of subjects within each age group • Range of doses within each age group • Sparse sampling for population PK approach • Adequate collection of covariate data (age, BW, gender)

  26. Lessons learned from FDA’s decade-long pediatric initiatives Outcome of well-designed pediatric PK/Safety studies: • Critical labeling changes that include unique pediatric dosing • Focus on drug clearance and its variability in children • Pediatric dosing not always obtained by simply applying BW or BSA based calculations to the adult dose • Systemic exposure in children not always predictable based on prior adult information

  27. Optimizing Pediatric Dosing: Desloratadine (Clarinex®) as an Example Dose determination from traditional PK analysis (NDA 21300) Dose prediction from Population PK analysis (NDA 21563) *CLpredicted / CLadult x adult dose

  28. Optimizing Pediatric Dosing: Desloratadine (Clarinex®) as an Example Dosing Recommendations: Adults and children ≥12 years: 5 mg once daily Children 6 to 11 years of age: 2.5 mg once daily Children 12 months to 5 years of age: 1.25 mg once daily Children 6 to 11 months of age: 1.0 mg once daily

  29. Summary (1) • No pediatric PK data for a large number of OTC cough and cold drugs • Based on the data we have, PSE, CHLOR and BROM monograph doses DO NOT appear to exhibit greater drug exposure in children relative to adults • As in adults, drug clearance is highly variable in children and not readily predictable based on prior adult information

  30. Summary (2) • Factors impacting clearance mechanisms in children: • ontogeny • genetic polymorphism • Post-mortem drug redistribution may partly explain high post-mortem levels in reported cases • To optimize pediatric dosing of OTC cough and cold drugs: should additional PK studies be conducted and if so, for which ingredients and what ages?

  31. Acknowledgements • Office of Clinical Pharmacology / Division of Clinical Pharmacology II • Emmanuel (Tayo) Fadiran, Ph.D. • Wei Qiu, Ph.D. • Suresh Doddapaneni, Ph.D. • Chandrahas Sahajwalla, Ph.D. • Sally Choe, Ph.D. • Abimbola Adebowale Ph.D.

  32. Back-Up Slides

  33. Example of Optimal Pediatric Dosing (1) Zosyn®: Application of Pop PK Analysis • Zosyn® is Piperacillin (PIP) /Tazobactam (TAZ), an IV antibacterial combination product • Eliminated via kidney • Comparable adult exposure as a basis for optimizing pediatric dosing • Pediatric dosing incorporated clearance maturation rate below the age of 9 months Data from 2 pediatric PK/safety studies Adopted from Tornoe et al. (2007) Int. J. Antimicrob. Agents, 30, 320–324.

  34. Example of Optimal Pediatric Dosing (2) Zosyn®: Application of Pop PK Analysis Dosing recommendation: Adults and children weighing >40 kg: 3.375 g every six hours totaling 13.5 g (12.0g PIP / 1.5g TAZ) per day. Children ≥ 9 months up to 40 kg: 100 mg PIP / 12.5 mg TAZ per kg, q 8h Children 2 to < 9 months: 80 mg PIP / 10 mg TAZ per kg, q 8h Adopted from Tornoe et al. (2007) Int. J. Antimicrob. Agents, 30, 320–324.

  35. Ontogeny of CYP3A4 in the 1st year of life: Fractional urinary recovery of 3-hydroxymorphinan (3HM) • Metabolic shift from DX (CYP2D6 metabolite) to 3HM (CYP 3A4 metabolite) Blake MJ (2007) Clin. Pharmacol. Ther. 2007, 81, 510-516

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