H-08

Drug Interaction Studies -- Study Design, Data Analysis, and Implications for Dosing and Labeling: Current Opinion

S. M. Huang¹ , K. S. Reynolds¹ , J. M. Strong² , S. Nallani¹ , L. J. Lesko¹ , R. Temple³ , S. Abraham¹ , S. Alhabet¹ , R. Baweja¹ , S. M. Chung¹ , P. Colangelo¹ , J. M. Collins² , D. Frucht² , M. D. Green⁴ , P. Hepp¹ , R. Kavanagh¹ , H. S. Ko⁵ , P. Marroum¹ , J. Norden³ , W. Qiu¹ , A. Rahman¹ , S. Sobel² , T. Stifano⁵ , X. Wei¹ , S. U. Yasuda¹ , L. K. Zhang¹ , J. H. Zheng¹ , ¹OCPB, CDER, FDA, ²OPS, CDER, FDA, ³OMP, CDER, FDA, ⁴OND, CDER, FDA, ⁵CBER, FDA

Purpose: Creation of a concept paper that reflects the Agency\\\'s current view that the metabolism of a new drug should be defined and its potential to interact with other drugs should be explored as part of the assessment of safety and effectiveness.

Methods: Latest scientific consensus on drug metabolism, drug transporters and pharmacokinetics was considered, based on discussions at conferences, advisory committee meetings, and consultation with experts.

Results: Evaluation of drug interactions involves an integration of in vitro and in vivo methods, as indicated by the decision tree in the concept paper.

In vitro methods: Concept paper describes principles of study conduct, including up to date information on in vitro induction studies. A list of probe CYP substrates, inhibitors and inducers is provided. Paper indicates specific results from in vitro studies that warrant in vivo investigation. In vitro studies that evaluate the potential for interactions related to drug transporters, particularly P-glycoprotein, are described.

In vivo methods: Concept paper includes details of study design and a list of probe CYP substrates, inhibitors and inducers. The paper also includes recommendations on the conduct of in vivo P-glycoprotein inhibition related interactions. Appropriate labeling language is discussed. The labeling discussion includes a list of CYP3A sensitive substrates and strong and moderate inhibitors, to help make labeling recommendations more consistent.

Conclusions:

The concept paper includes current recommendations for in vitro and in vivo drug metabolism and drug interaction studies performed during drug development. The decision tree emphasizes the integrated approach to evaluation of drug interactions

Reference: http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4079b1.htm (topic 2)