Clinical Pharmacology Subcommittee (CPSC) Report

ACPS 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 Pharmacology

Pharmacogenetics

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.

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

CPSC Meeting, November 17, 2003

• Clinical Trial Simulations (QT Studies) Speakers:

– P. Lee, Ph.D.– P. Bonate, Ph.D. (Ilex)– L. Kenna, Ph.D.

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?

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.

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

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)

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

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)

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