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.


CONCLUSIONS
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.
Greenblatt
D J
DJ
Department of Pharmacology, and Experimental Therapeutics, Tufts University School of Medicine, Boston, MA 02111, USA. Dgreenblatt@infonet.tufts.edu
von Moltke
L L
LL
Harmatz
J S
JS
Mertzanis
P
P
Graf
J A
JA
Durol
A L
AL
Counihan
M
M
Roth-Schechter
B
B
Shader
R I
RI
D000284:Administration, Oral; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D015725:Fluconazole / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D017964:Itraconazole / Q000494:pharmacology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000494:pharmacology*; D012016:Reference Values; D000077334:Zolpidem
D000935:Antifungal Agents; D006993:Hypnotics and Sedatives; D011725:Pyridines; D017964:Itraconazole; D000077334:Zolpidem; D015725:Fluconazole; D007654:Ketoconazole