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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
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

slide2
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.
slide3
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?
slide4
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?

slide5
Effect of Gemfibrozil

Statins

AUC ratios

c.f.

Trimethorprim

cerivastatin

repaglinide

fluvastatin

rosuvastatin

lovastatin acid

rosiglitazone

simvastatin acid

slide6
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?
slide7
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?
slide8
CYP2B6 and Drug Interactions

David A Flockhart, MD, PhD

Indiana University

CYP2C8 and Drug Interactions

Pertti J Neuvonen, MD

University of Helsinki

slide9
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?
slide10
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