ASSESSMENT OF FLUVOXAMINE EFFECTS ON THE PHARMACOKINETICS OF ZOLPIDEM AND ITS METABOLITE IN HEALTHY VOLUNTEERS

The objective of this study was to investigate the effects of fluvoxamine on the pharmacokinetics of zolpidem and its main metabolite, zolpidem phenyl-4-carboxylic acid (Z4CA) in healthy volunteers. The study consisted of 2 periods: Period 1 (Reference), when the volunteers received a single dose of 5 mg zolpidem and Period 2 (Test), when a combination of 5 mg zolpidem and 100 mg fluvoxamine was administered, after a pre-treatment regimen with fluvoxamine for 6 days. The pharmacokinetic parameters of zolpidem and its metabolite were determined by using non-compartmental methods. Pretreatment with fluvoxamine increased the mean peak plasma concentration (C-max) of zolpidem. Also, after concomitant intake of fluvoxamine, the total area under the curve (AUC(0-infinity)) was significantly increased from 340.34 +/- 249.02 to 725.05 +/- 429.23 ng*h/mL. As for Z4CA, C-max was reduced from 117.08 +/- 37.55 to 82.33 +/- 25.71 ng/mL. After fluvoxamine intake, the clearance of Z4CA was to some extent impaired as suggested by reducing the elimination rate constant (k(el)) and by prolonging its half-life (t(1/2)). This study demonstrated that fluvoxamine was responsible for a 2.13-fold exposure to zolpidem and influenced Z4CA pharmacokinetics to a lesser degree. The clinical implications of this interaction need additional studies.