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.

The Effect of Two Benzodiazepine Receptor Agonist Hypnotics on Sleep-Dependent Memory Consolidation

“…Thus morning testing occurred 9.5 h after zolpidem-ER dosing and 5.5 h after zaleplon dosing which is approximately 1.5 h after drug should have been eliminated based on pharmacokinetic data. 23,24 Both time intervals are consistent with prior studies of SDMC involving overnight sleep. 5,6 Polysomnography (PSG) was conducted at each of the 3 overnight visits with bedtime at the subject's reported typical bedtime and time in bed held constant at 8 hours.…”

“…The two hypnotics have similar mechanisms of action, both binding preferentially to the α-1 benzodiazepine receptor subunit, 22 although their durations of action differ. Zolpidem-ER has an estimated duration of action of 6-8 h, with a t 1/2 of 2.8 h and a t max of 1.5 h. 23 In contrast, zaleplon has an estimated duration of action of 3-4 h due to rapid absorption and elimination, with t 1/2 and t max both approximately one h. 24 These doses were chosen because, at the time of study, they were the recommended therapeutic doses for treatment of insomnia. In addition, residual morning sedation has not been detected with either drug at these doses when administered at bedtime, 25,26 or with zaleplon 10 mg when administered as little as 4 h before wake time (middle-of-the-night dosing).…”

A rapid and accurate UPLC/MS/MS method for the simultaneous determination of zolpidem and its main metabolites in biological fluids and its application in a forensic context

“…Previous studies have examined the pharmacokinetics of the Caucasian population after the oral administration of 10 mg zolpidem. Weinling et al reported that the C max of zolpidem in blood was 167 ± 34 ng/mL and the T max was 0.8-2.0 h. Similarly, Drover et al showed that the C max of zolpidem in blood was 167 ± 81 ng/mL and the T max 0.9-2.1 h [27,28]. These data suggest that the pharmacokinetics are different in the Caucasian and Chinese Han populations; our studies found a lower C max and a shorter T max compared with the reported pharmacokinetics in the Table 4 Pharmacokinetic parameters of zolpidem after a single oral dose of 10 mg drug.…”

Incorporation of Zolpidem into Hair and Its Distribution after a Single Administration

“…The exposure time of the hair bulb region to ZP in blood should have an essential effect on its incorporation. Although the time changes in ZP level in the blood of the subjects was not monitored, Weinling et al (2006) reported that a single oral dose in 24 healthy men attained peak plasma ZP concentrations at approximately 1.6 hours after intake, declining with an average elimination half-life of 2.8 hours. In this study, ZP in the 0-to 1-mm segment, including the bulb, was found to be more abundant at 24 hours than at 10 hours after intake.…”