Kinetic and dynamic interaction study of zolpidem with ketoconazole, itraconazole, and fluconazole

Background: Azole antifungal agents may impair hepatic clearance of drugs metabolized by cytochrome P450-3A isoforms. The imidazopyridine hypnotic agent zolpidem is metabolized in humans in part by P450-3A, as well as by a number of other cytochromes, Potential interactions of zolpidem with 3 commonly prescribed azole derivatives were evaluated in a controlled clinical study. Methods: In a randomized, double-blind, 5-way, crossover, clinical pharmacokinetic-pharmacodynamic study, 12 volunteers received (A) zolpidem placebo plus azole placebo, (B) 5 mg zolpidem plus azole Placebo (C) zolpidem plus ketoconazole, (D) zolpidem plus itraconazole, and (E) zolpidem plus fluconazole. Results: Mean apparent oral clearance of zolpidem when given with placebo was 422 mL/min, and elimination half-life was 1.9 hours. Clearance was significantly reduced to 250 mL/min when zolpidem was given with ketoconazole, and half-life was prolonged to 2.4 hours, Coadministration of zolpidem with itraconazole or fluconazole also reduced clearance (320 and 338 mL/min), but differences compared to the zolpidem plus placebo treatment did not reach significance. Zolpidem-induced benzodiazepine agonist effects (increased electrocardiographic beta activity, digit-symbol substitution test impairment, and delayed recall) during the first 4 hours after dosage were enhanced by ketoconazole but not by itraconazole or fluconazole, Conclusion: Coadministration of zolpidem with ketoconazole impairs zolpidem clearance and enhances its benzodiazepine-like agonist pharmacodynamic effects. Itraconazole and fluconazole had a small influence on zolpidem kinetics and dynamics. The findings are consistent with in vitro studies of differentially impaired zolpidem metabolism by azole derivatives.