Effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam.

AIMS: The aim of the study was to determine the effects of oral clotrimazole troches on the pharmacokinetics of oral and intravenous midazolam in the plasma. METHODS: We conducted a randomized, open-label, four-way crossover study in 10 healthy volunteers. Each volunteer received oral midazolam 2 mg or intravenous midazolam 0.025 mg kg(-1) with and without oral clotrimazole troches 10 mg taken three times daily for 5 days. Each study period was separated by 14 days. Serial blood samples were collected up to 24 h after oral midazolam and 6 h after intravenous midazolam. Plasma concentrations for midazolam and its metabolite 1-hydroxymidazolam were measured and fitted to a noncompartmental model to estimate the pharmacokinetic parameters. RESULTS: Ten healthy volunteers aged 21-26 years provided written informed consent and were enrolled into the study. Clotrimazole decreased the apparent oral clearance of midazolam from 57 +/- 13 l h(-1)[95% confidence interval 48, 66] to 36 +/- 9.8 l h(-1) (95% confidence interval 29, 43) (P= 0.003). These changes were accompanied by a decrease in the area under the concentration-time curve (mean difference 22 microg h(-1) l(-1), P= 0.001) and bioavailability (mean difference 0.21, P= NS). There were no significant differences in the systemic clearance of midazolam with or without clotrimazole troches. CONCLUSIONS: Oral clotrimazole troches decreased the apparent oral clearance of midazolam; no significant differences in the systemic clearance of midazolam were found.

Concomitant clotrimazole therapy more than doubles the relative oral bioavailability of tacrolimus.

The purpose of this pharmacokinetic study was to determine whether the relative oral bioavailability of tacrolimus is increased with concomitant administration of clotrimazole. Pharmacokinetic studies were conducted in 6 adult kidney transplant patients receiving tacrolimus therapy. Pharmacokinetic profiling was performed by blood sampling over 12 hours before and after the administration of a 5-day course of clotrimazole. Tacrolimus whole-blood concentrations were determined by microparticle enzyme immunoassay. Noncompartmental pharmacokinetic analysis was conducted using WinNonLin, Standard Edition, Version 1.1. Concomitant administration of clotrimazole more than doubled the relative oral bioavailability of tacrolimus. The mean AUC0-12 of tacrolimus was increased 250% with clotrimazole (467.0 +/- 170.0 ng.h/mL versus 188.7 +/- 50.2 ng.h/mL; P = 0.002). Tacrolimus blood trough concentrations also more than doubled with coadministration of clotrimazole (27.7 +/- 10.4 ng/mL versus 11.6 +/- 4.0 ng/mL; P = 0.003). Mean Cmax was significantly increased with clotrimazole (70.7 +/- 34.7 ng/mL versus 27.4 +/- 11.1 ng/mL, P = 0.01). Tmax decreased from 3.2 +/- 1.6 hours to 1.9 +/- 1.0 hours (P = NS). In addition, the apparent oral clearance decreased 60% with coadministration of clotrimazole (median oral clearance 0.16 L/h/kg versus 0.40 L/h/kg; P = 0.03). Thus, clotrimazole causes a significant increase in the relative oral bioavailability, Tmax, and trough concentration of tacrolimus. Tacrolimus levels should be monitored following initiation or discontinuation of clotrimazole to minimize toxicity or precipitation of an acute rejection episode due to subtherapeutic levels.