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CYP2B6/CYP2C8 and Drug Interactions: Introduction

Advisory Committee for Pharmaceutical Sciences - Clinical Pharmacology Subcommittee Meeting November 18, 2003, Rockville, MD. CYP2B6/CYP2C8 and Drug Interactions: Introduction . Shiew-Mei Huang, Ph.D. Deputy Director for Science Office of Clinical Pharmacology & Biopharmaceutics

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CYP2B6/CYP2C8 and Drug Interactions: Introduction

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  1. Advisory Committee for Pharmaceutical Sciences - Clinical Pharmacology Subcommittee Meeting November 18, 2003, Rockville, MD CYP2B6/CYP2C8 andDrug Interactions: Introduction Shiew-Mei Huang, Ph.D. Deputy Director for Science Office of Clinical Pharmacology & Biopharmaceutics CDER, FDA

  2. Drug Interaction Guidance (1999) Revision- • classification of CYP3A inhibitors • P-gp based interactions • in vitro evaluation • labeling implication • Guidance for industry: In vivo metabolism/drug interactions: Study design, data analysis and recommendation for dosing and labeling (Issued 11/24/1999, Posted 11/24/1999); http://www.fda.gov/cder/guidance/index.htm; http://www.fda.gov/cder/guidance/2635fnl.pdf • Tucker, Houston and Huang, Clin Pharm Ther August 2001; 70(2):103 • Bjornsson, Callaghan, Einolf, et al, J Clin Pharmacol, May 2003; 43(5):443 • Yuan, Madani, Wei, Reynolds, Huang, Drug Metab Disp, December 2002; 30(12) 1311 • Labeling guideline. Federal Register 65[247], 81082-81131. December 22, 2000.

  3. In vitro CYP evaluation Current Practices CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A - reaction phenotyping (in addition:2A6, 2B6, 2C8, 2E1) - enzyme modulating effect • In vivo (clinical) evaluation - Prioritized based on in vitro CYP results • other drugs’ effect • effect on other drugs - P-gp based interactions • Other pathways?

  4. Cases of rhabdomyolysis involving gemfibrozil and statins Why CYP2C8? • Pharmacodynamic/pharmacokinetic interaction? • Gemfibrozil does not interact via CYP3A • Other enzymes/transport pathway? - CYP2C8/2C9, UGT, OATP?

  5. Effect of Gemfibrozil Statins AUC ratios c.f. Trimethorprim cerivastatin repaglinide fluvastatin rosuvastatin lovastatin acid rosiglitazone simvastatin acid

  6. Drug A • What CYP2C8 inhibitors available to evaluate clinical significance of this type of interactions? • Metabolized by CYP2C8 in vitro Drug B • Inhibits CYP2C8 in vitro • What CYP2C8 probe substrates to evaluate clinical significance of this type of interactions?

  7. Why CYP2B6? • Recent data on inducers • Recent studies on efavirenz, bupropion Drug C • Metabolized by CYP2B6 in vitro • What CYP2B6 inhibitors available to evaluate clinical significance of this type of interactions?

  8. CYP2B6 and Drug Interactions David A Flockhart, MD, PhD Indiana University CYP2C8 and Drug Interactions Pertti J Neuvonen, MD University of Helsinki

  9. Issues to discuss - • What is the clinical significance of CYP2B6- and CYP2C8- based interactions? • Are there tools available for clinical evaluation of CYP2B6- and CYP2C8 based interactions? • Other areas to focus on?

  10. Drug Interactions working group Sophia Abraham Sayed Al-Habet Sang Chung Phil Colangelo Shiew-Mei Huang Ron Kavanagh Srikanth Nallani Lawrence Lesko Wei Qiu Atik Rahman Kellie Reynolds Xiaoxiong Wei Lei K Zhang Jenny H Zheng Jerry Collins Soloman SobelJohn Strong Martin Green David Frucht Kathy Hollinger

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