title: Pharmacokinetic profile of a new modified release formulation of zolpidem designed to improve sleep maintenance.
abstract: 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 t(max). With zolpidem-MR 12.5 mg, C(max) 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 t(max) and terminal half-life.
authors.affiliation: Sanofi-Synthelabo Research (Sanofi-Aventis group), Chilly-Mazarin, France. estelle.weinling@sanofi-aventis.com
authors.forename: Estelle
authors.initials: E
authors.lastname: Weinling
authors.forename: Stuart
authors.initials: S
authors.lastname: McDougall
authors.forename: Frédéric
authors.initials: F
authors.lastname: Andre
authors.forename: Gabrio
authors.initials: G
authors.lastname: Bianchetti
authors.forename: Catherine
authors.initials: C
authors.lastname: Dubruc
mesh_terms: D000284:Administration, Oral; D000328:Adult; D001682:Biological Availability; D018592:Cross-Over Studies; D003692:Delayed-Action Preparations; D006207:Half-Life; D006801:Humans; D006993:Hypnotics and Sedatives / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011725:Pyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D012016:Reference Values; D012890:Sleep / Q000187:drug effects*; D000077334:Zolpidem
chemical_list: D003692:Delayed-Action Preparations; D006993:Hypnotics and Sedatives; D011725:Pyridines; D000077334:Zolpidem