Dose-response evaluation of the interaction between sertraline and alprazolam in vivo

In vitro data show the inhibition of alprazolam metabolism by sertraline via CYP3A4; therefore, using a randomized, double-blind, placebo-controlled design, the authors conducted this study to assess the potential for similar in vivo inhibition in humans. Ten healthy volunteers participated in two test sessions (placebo/alprazolam 1 mg orally) before the initiation of sertraline treatment. Blood samples were obtained over a 32-hour period and pharmacodynamic measures (sedation, psychomotor performance, memory function) were obtained over an 8-hour period. After a minimum of 2 weeks of daily sertraline self-administration (50, 100, or 150 mg/day), test sessions were repeated. Alprazolam concentrations (N = 6, 4, and 6 at sertraline doses of 50, 100, and 150 mg/day, respectively) showed no significant changes based on peak concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (t1/2[beta]), and area under the concentration-time curve (AUC(0-8)), with the exception of a reduced Cmax in the 50 mg/day group. Similarly, dynamic data showed no significant variations based on peak effect, Tmax, and AUC(0-infinity), with the exception of increased peak impairment in one measure of psychomotor performance. No differences were detected between placebo alone and placebo plus sertraline. These findings suggest that sertraline (50-150 mg/day) does not alter the single-dose kinetics or dynamics of alprazolam; therefore, the combination may be prescribed without an increased risk of alprazolam toxicity.