Effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem

Abstract

Objective: Zolpidem is a short-acting␣imidazopyridine hypnotic which is biotransformed in humans mainly by CYP3A4. Itraconazole strongly interacts with many substrates of CYP3A4 such as midazolam and triazolam. In this study, the effect of itraconazole on the pharmacokinetics and pharmacodynamics of zolpidem was investigated to uncover a possible clinically significant interaction. Methods: In a randomized cross-over study with two phases, ten healthy volunteers took either 200 mg itraconazole or placebo once daily for 4 days. A single oral dose of 10 mg zolpidem was given on day 4. Plasma drug concentrations were measured up to 17 h and effects of zolpidem up to 9 h after the ingestion of zolpidem. Results: Itraconazole had no marked effects on the pharmacokinetics of zolpidem; the total area under the plasma zolpidem concentration–time curve (AUC_0–∞) was 34% larger during the itraconazole phase (759 ng · h · ml⁻¹) than during the placebo phase (567 ng · h · ml⁻¹). Exophoria of the eyes by the Maddox wing test was significantly increased by itraconazole, but the results of the digit symbol substitution test, critical flicker fusion test, postural sway tests and the visual analogue scale tests for subjective drowsiness and overall drug effect did not differ between the phases. Conclusion: The pharmacokinetics and pharmacodynamics of zolpidem were not remarkably affected by itraconazole in healthy volunteers. Therefore, unlike triazolam, for example, zolpidem can be used in normal or nearly normal doses together with itraconazole and probably also with other CYP3A4 inhibitors.