Effect of terbinafine and voriconazole on the pharmacokinetics of the antidepressant venlafaxine

This study investigated the effect of terbinafine and voriconazole on the pharmacokinetics of venlafaxine in healthy volunteers. Plasma concentrations of venlafaxine and O-desmethylvenlafaxine (ODV) were measured after ingestion of 75mg venlafaxine without pretreatment (control), after terbinafine pretreatment, or after voriconazole pretreatment. During the terbinafine phase, the area under the plasma concentration-time curve (AUC((0-infinity))) of venlafaxine was on average 490% (P < 0.001) and that of ODV 57% (P < 0.001) of the corresponding control value. Terbinafine decreased the AUC((0-infinity)) ratio of ODV over venlafaxine by 82% (P < 0.001). Voriconazole slightly increased the sum of AUC((0-infinity)) of venlafaxine plus AUC((0-infinity)) of ODV (active moiety) by 31% (P < 0.001). The most likely mechanism for the interaction between terbinafine and venlafaxine is the inhibition of CYP2D6-mediated O-demethylation of venlafaxine, whereas the minor effects of voriconazole are probably due to the inhibition of CYP3A4-, CYP2C9-, or CYP2C19-mediated metabolism of venlafaxine.