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Effect of Desvenlafaxine on the Cytochrome P450 2D6 Enzyme System

Preskorn, Sheldon H. MD*; Nichols, Alice I. PhD; Paul, Jeffrey PhD; Patroneva, Albena L. MD; Helzner, Eileen C. MD; Guico-Pabia, Christine J. MD, MBA, MPH

Journal of Psychiatric Practice®: November 2008 - Volume 14 - Issue 6 - p 368-378
doi: 10.1097/01.pra.0000341891.43501.6b

Background The cytochrome P450 2D6 (CYP2D6) enzyme is responsible for metabolizing approximately 25% of pharmaceutical agents. Individuals with impaired CYP2D6 metabolism and those concomitantly receiving agents that inhibit CYP2D6 can have variations in concentrations of such medications and their metabolites.

Methods Five studies assessing the interaction between desvenlafaxine and CYP2D6 are reviewed. Study 1 compared desvenlafaxine area under the plasma concentration-versus-time curve (AUC) in CYP2D6 extensive metabolizers (EMs) and poor metabolizers (PMs) after administration of 100 mg of desvenlafaxine or 75 mg of venlafaxine extended release (ER). Studies 2 to 5 assessed the effect of concomitant administration of desvenlafaxine 100 mg (studies 2, 4, and 5) or 400 mg (study 3), paroxetine (20 mg, study 4), and duloxetine (30 mg twice daily; study 5) on the CYP2D6 probe desipramine.

Results In study 1, there was no significant difference in mean desvenlafaxine AUC between the CYP2D6 EMs and PMs (−11%; P=0.641) who were administered desvenlafaxine. However, PMs receiving venlafaxine ER had significantly higher venlafaxine and lower desvenlafaxine AUCs compared with EMs (+350% and −74%, respectively; P<0.001 for each). In studies 2, 4, and 5, the mean increases in desipramine AUC with concomitant administration of desvenlafaxine 100 mg ranged from 17% to 36%; the increase with concomitant administration of desvenlafaxine 400 mg (study 3) was 90%. Paroxetine and duloxetine produced increases in mean desipramine AUC of 419% and 122%, respectively, which were significantly greater than the increases seen with desvenlafaxine 100 mg (P<0.001 for each comparison).

Conclusions Based on the findings presented here, desvenlafaxine is expected to have a low risk for variability in efficacy and safety/tolerability resulting from CYP2D6 polymorphisms or drug-drug interactions when coadministered with CYP2D6 substrates or inhibitors.

*Clinical Research Institute and University of Kansas School of Medicine, Wichita

Former employee of Wyeth Research

Wyeth Research, Collegeville, PA

Please send correspondence and reprint requests to: Sheldon H. Preskorn, MD, Clinical Research Institute, 201 S. Hillside, Wichita, KS 67211.

Funding Information and Disclosures: Over his career, Dr Preskorn has served or is serving in one or more of the following capacities, as a principal investigator, on the speakers bureau, and/or as a consultant for the following companies: Abbott Laboratories, AstraZeneca, Aventis, Biovail, Boehringer-Ingleheim, Bristol-Myers Squibb, E. Merck, Eisai, Eli Lilly, Glaxo-SmithKline, Hoffman LaRoche, Janssen, Johnson & Johnson, Lundbeck, Merck, Neurosearch, Novartis, Organon, Otusak, Pfizer, Inc., Solvay, Sommerset, Sumitomo, Wyeth, and Yamanouchi. Drs Nichols, Paul, Helzner, and Guico-Pabia are employees of Wyeth Research. Drs Helzner, Guico-Pabia, and Paul have disclosed that they own stock or stock options in Wyeth. Dr Patroneva is a former employee of Wyeth Research.

© 2008 Lippincott Williams & Wilkins, Inc.