Pharmacokinetic and Pharmacodynamic Evaluation of the Potential Drug Interaction Between Venlafaxine and Diazepam

Abstract

To assess possible pharmacokinetic and pharmacodynamic interactions between the antidepressant venlafaxine and diazepam, a randomized, two-period, crossover study was conducted in 18 men. Multiple-dose venlafaxine (50 mg every 8 hours) or placebo (double-blind) was given for 10 days; on day 4 a single placebo dose (same appearance as diazepam capsule, single-blind) was given; and on day 5 a single dose of diazepam (10 mg) was given. Pharmacokinetic data indicated that diazepam had no significant effect on venlafaxine or O-desmethylvenlafaxine disposition. Diazepam pharmacokinetics were minimally changed in the presence of venlafaxine. Diazepam oral clearance (CL/f) increased slightly (24 +/- 8 versus 26 +/- 6 mL/h/kg; P = .007), volume of distribution (Vz/f) increased (0.85 +/- 0.28 versus 0.99 +/- 0.34 L/kg; P = .02), and AUC decreased (5973 +/- 2304 versus 5008 +/- 1354 ng.h/mL; P = .02). Venlafaxine did not alter desmethyldiazepam pharmacokinetics. Pharmacodynamic data showed a statistically significant diazepam-venlafaxine interaction for only one of the eight psychometric tests given. Critical flicker fusion slightly decreased (P = .01) between placebo-diazepam (37.85 +/- 3.28 Hz) and venlafaxine-diazepam (37.09 +/- 4.13 Hz) treatments. The observed pharmacokinetic and pharmacodynamic interactions between diazepam and venlafaxine were small and probably clinically insignificant.

New antidepressants and the cytochrome P450 system: Focus on venlafaxine, nefazodone, and mirtazapine

“…When subjects pretreated with multiple dose venlafaxine (150 mg in divided doses) or placebo received a single 5 mg dose of diazepam, the antidepressant increased diazepam clearance and volume of distribution and decreased diazepam AUC (Troy et al, 1995). Critical flicker fusion scores were also reported as altered, though reanalysis of the data revealed that immediate word recall scores were altered instead.…”

Venlafaxine compromises the antinociceptive actions of gabapentin in rat models of neuropathic and persistent pain

“…Whereas gabapentin has not been reported to interact negatively with other drugs, several examples have been detailed with venlafaxine (Amchin et al 1998a,b;Levin et al 2001;Troy et al 1995). Venlafaxine is thought to be a substrate for CYP3A4, but as gabapentin is excreted 99.8% unchanged via the kidneys in rats (Radulovic et al 1995), this is an unlikely mechanism for the interaction observed.…”

Alternative venlafaxine kinetics in overdose

“…Previous studies suggest that these patients are more prone to adverse drug events (6). Pharmacokinetic studies of venlafaxine which have compared the ratio of mean steady state AUC (O‐DV): AUC (venlafaxine) have demonstrated a range from 1·5 to 4·1 (4, 7, 8). In our subject the ratio of total AUCs of O‐DV to venlafaxine was 0·88, suggesting the possibility that our patient was a poor metabolizer.…”