# Presentation: 841799

##  CYP2B6/CYP2C8 andDrug Interactions: Introduction  

**Shiew-Mei Huang, Ph.D.**
**Deputy Director for Science**
**Office of Clinical Pharmacology & Biopharmaceutics**
**  ****CDER, FDA**

**Advisory Committee for Pharmaceutical Sciences **
**- Clinical Pharmacology Subcommittee Meeting**
**November 18,  2003, Rockville, MD**

## 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/index.htm)_**; **_[http://www.fda.gov/cder/guidance/2635fnl.pdf](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.   **

## In vitro CYP evaluation 

**- reaction phenotyping (****in addition:**** *****2A6, 2B6, 2C8, 2E1*****)**
**- enzyme modulating effect**

_**CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A**_** **

**Current Practices**

**In vivo (clinical) evaluation**

**other drugs’ effect**
**effect on other drugs**

**Other pathways? **

**- Prioritized based on **
**	****in vitro CYP results **

**- P-gp based interactions**

## Cases of rhabdomyolysis involving gemfibrozil and statins

**Gemfibrozil does not interact via CYP3A**

**Pharmacodynamic/pharmacokinetic interaction?**

**Other enzymes/transport pathway?**

**- CYP2C8/2C9, UGT, OATP?**

**Why CYP2C8?**

## Effect of Gemfibrozil

**fluvastatin**

**Effect of Gemfibrozil**

**cerivastatin**

**simvastatin acid**

**rosiglitazone**

**repaglinide**

**AUC ratios**

**c.f.**
**Trimethorprim**

**rosuvastatin**

**lovastatin acid**

**Statins**

## Metabolized by CYP2C8 in vitro

**Metabolized by CYP2C8 in vitro**

**What **_**CYP2C8 inhibitors**_** available to evaluate clinical significance of this type of interactions?**

**What **_**CYP2C8 probe substrates**_** to evaluate clinical significance of this type of interactions?**

**Drug B**

**Inhibits CYP2C8 in vitro**

## Recent studies on efavirenz, bupropion

**Recent studies on efavirenz, bupropion**

**What **_**CYP2B6 inhibitors**_** available to evaluate clinical significance of this type of interactions?**

**Drug C**

**Metabolized by CYP2B6 in vitro**

**Recent data on inducers **

## David A Flockhart, MD, PhD
Indiana University

**David A Flockhart, MD, PhD**
**Indiana University**

**CYP2C8 and Drug Interactions**

**Pertti J Neuvonen, MD**
**University of Helsinki**

## What is the clinical significance of CYP2B6- and CYP2C8- based interactions?

**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?**

## 	Drug Interactions working group

**Jerry Collins ****	****Soloman Sobel** 	 **John Strong****	**

**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**

**Martin Green****	****David Frucht**

**Kathy Hollinger**

**	****Drug Interactions working group**