Dynamics and kinetics of a modified-release formulation of zolpidem: Comparison with immediate-release standard zolpidem and placebo

Modified-release (MR) zolpidem was developed to maintain effective plasma concentrations during the 3- to 6-hour post-dosage interval, corresponding to the middle portion of the typical sleep interval. Modified-release zolpidem (12.5 mg), standard immediate-release (IR) zolpidem (10 mg), and placebo were compared in a double-blind, single-dose, 3-way crossover daytime study of healthy volunteers (n = 70 completers). Effect areas for electroencepholographic beta amplitude during 0 to 8 hours and 3 to 6 hours after dosage were greater for MR compared to IR (P <.001). The digit-symbol substitution test and sedation rating scales behaved similarly. MR and IR did not differ in effects at 8 hours post-dosage nor in half-life or clearance. Time of peak plasma concentration (t(max)) was significantly longer for MR (2.4 vs 2.0 hours, P <.004), and dose-normalized peak plasma concentration (C-max) was lower (12.2 vs 14.0 ng/mL/mg, P <.001). MR zolpidem also had greater area under the plasma concentration curve (AUC) during the 3- to 6-hour interval (P <.001). Thus, MR zolpidem produces sustained plasma levels compared to IR, with resulting enhancement of pharmacodynamic effects in the 3- to 6-hour post-dosage interval.