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

From the Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and Tufts-New England Medical Center, Boston, Massachusetts (Dr Greenblatt, Mr Harmatz); Sanofi-Aventis Research, Clinical Pharmacology, Great Valley, Pennsylvania (Dr Legangneux); Sanofi-Aventis Research, Pharmacokinetics, Chilly Mazarin, France (Dr Weinling); and Clinilabs, New York, New York (Dr Freeman, Dr Rice, Dr Zammit).

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 doubleblind, single-dose, 3-way crossover daytime study of healthy volunteers (n = 70 completers). Effect areas for electroencephalographic ß 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 (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.

Key Words: Zolpidem • modified release • electroencephalography • pharmacokinetics • pharmacodynamics

Address for reprints: David J. Greenblatt, MD, Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, 136 Harrison Avenue, Boston, MA 02111; e-mail: dj.greenblatt{at}tufts.edu.