Dynamics and Kinetics of a Modified‐Release Formulation of Zolpidem: Comparison With Immediate‐Release Standard Zolpidem and Placebo

Modified‐release zolpidem produces sustained plasma levels compared to IR, with resulting enhancement of pharmacodynamic effects in the 3‐ to 6‐hour post‐dosage interval.

Abstract

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 electroencephalographic 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 halflife or clearance. Time of peak plasma concentration (tmax) was significantly longer for MR (2.4 vs 2.0 hours, P < .004), and dose-normalized peak plasma concentration (Cmax) 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.