Objective  

To study the influence of CYP3A4 inhibition by ketoconazole on the disposition of venlafaxine in individuals with different CYP2D6 pheno- and genotypes.

Methods  

In an open two-phase study, 21 healthy volunteers with known CYP2D6 pheno- and genotype [14 extensive metabolisers (EMs), 7 poor metabolisers (PMs)] were given a single oral dose of venlafaxine (50 mg to EMs and 25 mg to PMs). Plasma and urine levels of venlafaxine and its three metabolites were measured and the pharmacokinetics of venlafaxine were determined. After a 2-week washout period, subjects were treated for 2 days with ketoconazole (100 mg twice daily) starting 1 day before the administration of venlafaxine; and the same parameters as for the administration of venlafaxine only were measured.

Results  

Data were evaluated from 20 subjects (14 EMs and 6 PMs) who completed the study. The dose-corrected AUC of venlafaxine was on average 2.3 times higher (P<0.01) and that of its active metabolite O-desmethylvenlafaxine 3.4 times lower (P<0.0001) in PMs than EMs. There was a good correlation between the debrisoquine metabolic ratio and the ratio between the AUC of venlafaxine and that of O-desmethylvenlafaxine (Rs=0.93, P<0.002). The majority of subjects showed higher plasma levels of venlafaxine and O-desmethylvenlafaxine upon co-administration of ketoconazole. AUC of venlafaxine significantly increased by 36% and that of O-desmethylvenlafaxine by 26% (P<0.01). C_max values increased by 32% and 18%, respectively. The elimination half-life of venlafaxine was unaltered. Three of the PMs displayed marked increases in AUC (81, 126 and 206%) and C_max (60, 72, 119%) of venlafaxine while the other three showed small or no changes.

Conclusions  

Ketoconazole consistently affected the disposition of venlafaxine in EMs of debrisoquine while the response in PMs was erratic. The precise mechanisms underlying this interaction remain to be elucidated.