Dronedarone in high-risk permanent atrial fibrillation.

BACKGROUND: Dronedarone restores sinus rhythm and reduces hospitalization or death in intermittent atrial fibrillation. It also lowers heart rate and blood pressure and has antiadrenergic and potential ventricular antiarrhythmic effects. We hypothesized that dronedarone would reduce major vascular events in high-risk permanent atrial fibrillation. METHODS: We assigned patients who were at least 65 years of age with at least a 6-month history of permanent atrial fibrillation and risk factors for major vascular events to receive dronedarone or placebo. The first coprimary outcome was stroke, myocardial infarction, systemic embolism, or death from cardiovascular causes. The second coprimary outcome was unplanned hospitalization for a cardiovascular cause or death. RESULTS: After the enrollment of 3236 patients, the study was stopped for safety reasons. The first coprimary outcome occurred in 43 patients receiving dronedarone and 19 receiving placebo (hazard ratio, 2.29; 95% confidence interval [CI], 1.34 to 3.94; P=0.002). There were 21 deaths from cardiovascular causes in the dronedarone group and 10 in the placebo group (hazard ratio, 2.11; 95% CI, 1.00 to 4.49; P=0.046), including death from arrhythmia in 13 patients and 4 patients, respectively (hazard ratio, 3.26; 95% CI, 1.06 to 10.00; P=0.03). Stroke occurred in 23 patients in the dronedarone group and 10 in the placebo group (hazard ratio, 2.32; 95% CI, 1.11 to 4.88; P=0.02). Hospitalization for heart failure occurred in 43 patients in the dronedarone group and 24 in the placebo group (hazard ratio, 1.81; 95% CI, 1.10 to 2.99; P=0.02). CONCLUSIONS: Dronedarone increased rates of heart failure, stroke, and death from cardiovascular causes in patients with permanent atrial fibrillation who were at risk for major vascular events. Our data show that this drug should not be used in such patients. (Funded by Sanofi-Aventis; PALLAS ClinicalTrials.gov number, NCT01151137.).

Dynamics and kinetics of a modified-release formulation of zolpidem: comparison with immediate-release standard zolpidem and placebo.

Modified-release (MR) zolpidem was developed to maintain 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) zolpidem (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 beta amplitude during 0 to 8 hours and 3 to 6 hours after dosage were greater for MR compared 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 halflife or clearance. Time of peak plasma concentration (tmax) was significantly longer for MR (2.4 vs 2.0 hours, P < .004), and dose-normalized peak plasma concentration (Cmax) was lower (12.2 vs 14.0 ng/mL/mg, P < .001). MR zolpidem also had greater area under the plasma concentration 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.

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

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.