¹Department of Pharmacology and Experimental Therapeutics and the Division of Clinical Pharmacology, Tufts University School of Medicine and New England Medical Center Hospital, Boston, Mass and Boston Research and Science Consulting, Dover,Mass

Correspondence: David J. Greenblatt, MD, Department of Pharmacology, and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Ave, Boston, MA 02111. E-mail: Dgreenblatt@infonet.tufts.edu

^*Dr. von Moltke is the recipient of a Scientist Development Award (K21-MH-01237) from the Department of Health and Human Services.

^*Supported in part by grants MH-34233 and DA-05258 from the Department of Health and Human Services, by grant RR-00054 supporting the General Clinical Research Center. Tufts University School of Medicine and New England Medical Center Hospital, and by a grant-in-aid from Lorex Pharmaceuticals, Chicago, Ill.

Received 30 June 1998; Accepted 18 September 1998.

Abstract

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.