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.