Comparison of the Pharmacokinetics of Venlafaxine Extended Release and Desvenlafaxine in Extensive and Poor Cytochrome P450 2D6 Metabolizers

Background: The goal of this study was to evaluate the impact of cytochrome P450 2D6 extensive metabolizer (EM) or poor metabolizer (PM) status on the pharmacokinetics of single (loses of venlafaxine extended release (ER) and desvenlafaxine (administered as desvenlafaxine succinate) in healthy, adults. Methods: In an open-label. crossover study, 14 healthy volunteers (aued 18-55 year,;. 7 EMs and 7 PMs) received, in randomized sequence, single doses of venlafaxine FR 75 mg/d or desvenlafaxine 100 mg/d. Cytochrome P450 2D6 genotyping was performed, and plasma drug levels were measured. The arithmetic means and standard deviation (SD) for area under the plasma concentration-curve (AUC) and peak, plasma concentration (C-max) were calculated. Comparisons of AUC and C-max between cytochrome P450 2D6 EMs and PMs were calculated using a Wilcoxon exact test. Results: After administration of venlafaxine ER, mean C-max and AUC of venlafaxine were significantly greater in PMs compared with EM's, whereas mean C-max and AUC of its metabolite, desvenlafaxine. were siLnificantly lower for PMs than for EMs (P = 0.001. all comparisons). In contrast. mean C-max and AUC of desvenlafaxine after administration of desvenlafaxine were comparable between EMs and PMs. Conclusions: Cytochrome P450 2D6 genetic polymorphisms had no discernible impact Oil exposure to desvenlafaxine after desvenlafaxine administration: in contrast, compared with an EM phenotype, a PM phenotype had a significant effect oil venlafaxine and desvenlafaxine Plasma concentrations after venlafaxine ER administration. This reduced pharmacokinetic variability of desvenlafaxine may translate into better uniformity of response for patients receiving desvenlafaxine versus venlafaxine. but additional Studies are required to test this hypothesis.