ADVISORY COMMITTEE FOR PHARMACEUTICAL SCIENCE

Clinical Pharmacology Subcommittee

November 17 – 18, 2003

Rockville, MD

Background Information

Questions to the Committee for November 2003 CPSC Meeting – Draft 10/17/03

Topic 1 Quantitative analyses using exposure-response (Part A: EOP2A meeting)

Concept Paper. End-Of-Phase-2A Meetings with Sponsors Regarding Exposure-Response of IND and NDA Products. Draft 10/16/2003. (PDF) (HTM) (Word)

Quantitative analyses using exposure-response (Part B: QT study design)

Bonate, P. Rank Power of Metrics Used to Assess QTc Interval

Prolongation by Clinical Trail Simulation. J Clin Pharmacol 2000.

40:468-474

Topic 2 Pediatric bridging (Part A: Pediatric decision tree)

Guidance for Industry: Exposure-Response Relationships – Study

Design, Data Analysis, and Regulatory Applications. 3/2003.

Pediatric bridging (Part B: Pediatric population PK studies)

1. Machado, S. Methods for Determining Similarity of Exposure-

Response Between Pediatric and Adult Populations. Power Point

slides. 11/2003.

2. Lee, P., H. Sun, and L. Lesko. Design of Pediatrics Population

Pharmacokinetic Studies: Study Power, Precision, and Accuracy.

Draft 10/16/03 (PDF) (Word)

Topic 3 Drug interactions: Interactions involving CYP2B6 and CYP2C8

1. Wang, J., M. Neuvonen, X. Wen, J. Backman and P. Neuvonen.

Gemfibrozil Inhibits CYP2C8-Mediated Cerivastatin Metabolism

in Human Liver Microsomes. Drug, Metabolism and Disposition

2002. DMD 30:1352-1356

2. Niemi, M., J.T. Backman, M. Neuvonen, P.J. Neuvonen. Effects of

gemfibrozil, itraconazole, and their combination on the

pharmacokinetics and pharmacodynamics of repagelinide:

potentially hazardous interaction between gemfibrozil and

repaglinide. Diabetologia 2003. 46:347-351

3. Backman, J.T., C. Kyrklund, M. Neuvonen and P. Neuvonen.

Gemfibrozil greatly increases plasma concentrations of Cerivastatin. Department of Clinical Pharmacology, University of Helsinki and Helsinki University Central Hospital. American Society for Clinical Pharmacology and Therapeutics. 2002

4. Niemi, M., J.T. Backman, M. Granfors, J. Laitila, M. Neuvonen,

P.J. Neuvonen. Gemfibrozil considerably increases the plasma concentrations of rosiglitazone. Diabetologia 2003. 46:1319-1323

5. Wen, X., J. Wang, J.T. Backman, J Laitila, and P. Neuvonen.

Trimethoprim and Sulfamethoxazole are Selective Inhibitors of CYP2C8 and CYP2C9, Respectively. Drug, Metabolism and Disposition 2002. DMD 30:631-635

6. Ward, B., J. Gorski, D. Jones, S. Hall, D. Flockhart, and Z. Desta.

The Cytochrome P450 2B6 (CYP2B6) Is the Main Catalyst of Efavirenz Primary and Secondary Metabolism: Implication for HIV/AIDS Therapy and Utility of Efavirenz as a Substrate Marker of CYP2B6 Catalyst Activity. The Journal of Pharmacology and Experimental Therapeutics. 3/28/2003. JPET 306:287-300

Topic 4 Pharmacogenetics: Integration into new drug development