PHARMACOKINETICS AND PHARMACODYNAMICS J Clin Pharmacol 2006;46:1469-1480 1469 Modified-release (MR) zolpidem was developed to main- tain 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) zolpi- dem (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 β amplitude during 0 to 8 hours and 3 to 6 hours after dosage were greater for MR com- pared 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 concentra- tion (C max ) was lower (12.2 vs 14.0 ng/mL/mg, P < .001). MR zolpidem also had greater area under the plasma con- centration 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. Keywords: Zolpidem; modified release; electroencephalog- raphy; pharmacokinetics; pharmacodynamics Journal of Clinical Pharmacology, 2006;46:1469-1480 ©2006 the American College of Clinical Pharmacology Dynamics and Kinetics of a Modified-Release Formulation of Zolpidem: Comparison With Immediate-Release Standard Zolpidem and Placebo David J. Greenblatt, Eric Legangneux, Jerold S. Harmatz, Estelle Weinling, Jon Freeman, Kathleen Rice, and Gary K. Zammit T he duration of action of hypnotic drugs is a crit- ical determinant of their therapeutic effective- ness as well as adverse reactions. Drugs with an excessively long duration of action may be associ- ated with significant residual daytime effects such as impairment of performance on tasks such as dri- ving and using precision tools, as well as producing subjective daytime feelings of sedation and poor concentration. On the other hand, drugs with an excessively short duration of action may not allow adequate sleep maintenance in the later stages of the night. Duration of action is principally determined by the pharmacokinetic characteristics of the drug. 1,2 Older benzodiazepine hypnotics (in particular flu- razepam) caused significant residual daytime effects due to biotransformation to persistent biologically active metabolites. 3-7 The problem has been over- come to a large extent with newer hypnotics that do not have active metabolites and have a relatively short elimination half-life (t ½ ). The triazolobenzodiazepine triazolam was the first of the short half-life hypnotics. 1,2 Triazolam became extensively used in the 1980s and into the early 1990s. The imidozopyridine derivative zolpidem was 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). Submitted for publication April 19, 2006; revised version accepted July 21, 2006. Address for correspon- dence: 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@tufts.edu. DOI: 10.1177/0091270006293303