Pharmacokinetic profile of a new modified release formulation of zolpidem designed to improve sleep maintenance

• Published in: Fundamental & clinical pharmacology Vol. 20; no. 4; pp. 397 - 403
• Main Authors: Weinling, Estelle, McDougall, Stuart, Andre, Frédéric, Bianchetti, Gabrio, Dubruc, Catherine
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.08.2006; Blackwell
• Subjects: Administration, Oral; Adult; bioavailability; Biological and medical sciences; Biological Availability; Cross-Over Studies; Delayed-Action Preparations; Half-Life; Humans; Hypnotics and Sedatives - administration & dosage; Hypnotics and Sedatives - adverse effects; Hypnotics and Sedatives - blood; Hypnotics and Sedatives - pharmacokinetics; Infusions, Intravenous; Male; Medical sciences; Middle Aged; Models, Biological; modified release; pharmacokinetics; Pharmacology. Drug treatments; Pyridines - administration & dosage; Pyridines - adverse effects; Pyridines - blood; Pyridines - pharmacokinetics; Reference Values; Sleep - drug effects; zolpidem; Agonist; Controlled release form; Gabaergic agonist; Hypnotic; Benzodiazepine receptor; Bioavailability; Design; Sleep; Formulation; Dosage form; Zolpidem; Sleep wake cycle; Sedative; Pharmacokinetics; Gabaergic receptor A; modified release
• ISSN: 0767-3981; 1472-8206
• DOI: 10.1111/j.1472-8206.2006.00415.x

The aim of this study was to compare the relative bioavailability and the pharmacokinetic profile of a single oral dose of a zolpidem modified‐release (MR) 12.5‐mg formulation with those of the standard 10‐mg zolpidem immediate‐release (IR) formulation. Absolute bioavailabilities of oral formulations were evaluated using intravenously (i.v.) administered zolpidem as a reference. Twenty‐four healthy, Caucasian, male volunteers (18–45 years old) received single doses of three oral formulations (zolpidem‐MR 12.5 mg, zolpidem‐IR 10 mg and an experimental form) and zolpidem i.v. infusion (8 mg) in a randomized, open‐label, crossover trial. Blood samples (18 time‐points) were collected up to 16 h post‐dose after oral administration and up to 12 h post‐dose after i.v. administration. Pharmacokinetic parameters were determined by non‐compartmental analysis, allowing comparisons between treatments based on estimated ratios and differences, with 90% confidence intervals. The initial absorption phase of the zolpidem‐MR formulation was as fast as that of zolpidem‐IR with no significant difference in tmax. With zolpidem‐MR 12.5 mg, Cmax was moderately lower than with zolpidem‐IR (ratio of 0.82), and plasma zolpidem concentrations were maintained above those observed with zolpidem‐IR for a longer period of time, particularly from 3 to 6 h post‐dose. This was confirmed by an increase in half‐value duration (HVD) from 2.3 h with zolpidem‐IR to 4.6 h with zolpidem‐MR 12.5 mg. The mean terminal half‐life was similar between formulations. Zolpidem‐MR 12.5 mg provides the appropriate pharmacokinetic characteristics to extend plasma zolpidem concentrations into the middle of the night (3–6 h post‐dose), while retaining the same tmax and terminal half‐life.