Effects of steady-state clarithromycin on the pharmacokinetics of zolpidem in healthy subjects

Zolpidem is extensively metabolized by CYP3A4, CYP2C9 and CYP1A2. Previous studies demonstrated that pharmacokinetics of zolpidem was affected by CYP inhibitors, but not by short-term treatment of clarithromycin. The objective of this study was to investigate the effects of steady-state clarithromycin on the pharmacokinetics of zolpidem in healthy subjects. In the control phase, 33 subjects received a single dose of zolpidem (5 mg). One week later, in the clarithromycin phase, the subjects received clarithromycin (500 mg) twice daily for 5 days to reach steady state concentrations, followed by zolpidem (5 mg) and clarithromycin (500 mg). In each phase, plasma concentrations of zolpidem were evaluated up to 12 h after drug administration by using liquid chromatography-tandem mass spectrometry method. In the clarithromycin phase, mean total area under the curve of zolpidem (AUC(inf)) was 1.62-fold higher and the time to reach peak plasma concentration of zolpidem (t(max)) was prolonged by 1.95-fold compared to the control phase. In addition, elimination half-life (t(1/2)) of zolpidem was 1.40-fold longer during co-administration with clarithromycin and its apparent oral clearance (CL/F) was 36.2% lower with clarithromycin administration. The experimental data demonstrate the significant pharmacokinetic interaction between zolpidem and clarithromycin at steady-state.