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 (V_z/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.