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CPSC Meeting, November 17, 2003

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CPSC Meeting, November 17, 2003

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  1. Clinical Pharmacology Subcommittee (CPSC) ReportACPS Presentation, April 13, 2004Jürgen Venitz, MD, Ph.D.Goals of the Advisory Subcommittee:To provide expertise and feedback to ACPS, specifically in the areas of:Exposure-Response Modeling (Pharmacometrics)Pediatric Clinical PharmacologyPharmacogenetics

  2. CPSC Meeting, November 17, 2003 • Proposal for EOP2a Meetings (Speakers): • L. Lesko, Ph.D. • P. Lee, Ph.D. • Case Reports: • A. Parekh, Ph.D. • H. Ahn, Ph.D. • J. Gobburu, Ph.D.

  3. CPSC Meeting, November 17, 2003 • Proposal for EOP2a Meetings: • Pilot program to improve optimal dose finding • Additional FDA resources required • Integration of clinical/preclinical PK/PD (BM) information • Early identification of problem issues and utility function • Likely outcome measure: customer satisfaction, post-approval dose changes

  4. CPSC Meeting, November 17, 2003 • Clinical Trial Simulations (QT Studies) Speakers: • P. Lee, Ph.D. • P. Bonate, Ph.D. (Ilex) • L. Kenna, Ph.D.

  5. CPSC Meeting, November 17, 2003 • Clinical Trial Simulations (QT Studies): • QTc correction methods still questionable • Separation of baseline/random changes from drug-induced changes • “Meaningful QTc change”? • CTS may provide more rational risk/benefit assessment • DDI studies – PD interaction?

  6. CPSC Meeting, November 17, 2003 • Pediatric Decision Tree (Speakers): • Case Reports: • P. Hinderling, MD, Ph.D., • A, Chen, Ph.D. • S. Machado, Ph.D. • G. Kearns, Pharm.D.,Ph.D. (CPSC) • W. Rodriguez, M.D.

  7. CPSC Meeting, November 17, 2003 • Pediatric Decision Tree: • Appropriate PD endpoints in children (MOA, POD)? • Disease progression (POD) in children versus adults? • Incorporation of nonclinical information (primate, in-vitro) • Extensive interaction/interpretation between OCPB and reviewing division • Limitations of exposure-response • Work in progress

  8. CPSC Meeting, November 18, 2003 • Metabolic Drug-Drug Interactions (Speakers): • S.M. Huang, Ph.D. • CYP2B6: D. Flockhart, MD, Ph.D. (CPSC) • CYP2C8: P. Neuvonen, MD (U. of Helsinki)

  9. CPSC Meeting, November 18, 2003 • Metabolic Drug-Drug Interactions: • CYP2B6: • Substrates (in-vitro/in-vivo): efavirenz, bupropion • Inhibitor (in-vitro): thio-TEPA • No specific in-vivo inhibitors • CYP2C8: • Substrate (in-vitro/in-vivo): repaglinide • Inhibitors (in-vitro/in-vivo): gemfibrozil, trimethoprim • Multiple DDIs: • Population-based clinical studies • Medication-use database review to assess clinical significance of DDIs

  10. CPSC Meeting, November 18, 2003 • Pharmacogenetics: Integration in Drug Development (Speakers): • D. Flockhart, MD, Ph.D. (CPSC) • R. Hockett, MD (Eli Lilly) • M.V. Relling, Pharm.D. (CPSC)

  11. CPSC Meeting, November 18, 2003 • Pharmacogenetics: Integration in Drug Development: • Population-based study for prevalence of rare genetic polymorphisms needed • Mechanistic/quantitative understanding necessary for labeling • Impact on safety/efficacy and risk benefit • Level of PG detail on label – controversial • Multidimensional clinical covariate

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