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.).

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.

Background: This two-way, randomized, single-dose, crossover study determined the pharmacokinetics and absolute oral bioavailability of telithromycin in young and elderly healthy subjects. Methods: Twelve young (18–40 years) and 12 elderly (>65 years and ≤85 years) subjects received a single 800-mg oral dose of telithromycin or an intravenous infusion of 400 mg (young subjects) or 480 mg (elderly subjects) of telithromycin over 2.5 h in two treatment periods, separated by a 1-week washout period. The plasma concentrations and pharmacokinetic parameters of telithromycin and its major metabolite, RU 76363, were determined. Absolute oral bioavailability was calculated using the area under the plasma concentration-time curve (AUC) from zero hours to infinity. Results: The absolute oral bioavailability of telithromycin was 57% in both young and elderly subjects. The AUC for the metabolite was lower after intravenous infusion of telithromycin, indicating first-pass loss following oral administration. Telithromycin was well tolerated in both groups of subjects. Conclusions: Telithromycin has an absolute oral bioavailability of 57% in young and elderly subjects and is well tolerated.

Aims/Background To evaluate relative bioavailability and plasma pharmacokinetic (PK) profile of single oral doses of zolpidem modified‐release (MR) formulations (10 mg and 12.5 mg) compared to standard zolpidem 10 mg. Methods 24 healthy, Caucasian, male volunteers (18–45 years old) received single oral doses of zolpidem MR 10 mg and 12.5 mg, or standard zolpidem 10 mg via a randomized, open‐label, crossover study. Blood sample (n=18) were collected up to 16h postdose. PK parameters were determined by noncompartmental analysis: Cmax, tmax, t1/2z, AUC, MRT, and half‐value duration (HVD). Comparisons between treatments were performed by ANOVA (α=0.05). Results The initial absorption phase of zolpidem MR formulations was as fast as that of standard zolpidem with no significant difference in tmax. With zolpidem MR 12.5 mg, Cmax values were moderately lower (ratio of 0.82) compared with standard zolpidem and plasma concentrations were maintained above those observed with standard zolpidem for a longer period of time, and particularly from 3 to 6h postdose. This was confirmed by an increase of the HVD from 2.3h for standard zolpidem to 4.6h for zolpidem MR 12.5 mg. The mean terminal half‐life was similar with all 3 formulations. Conclusion These results show that this new zolpidem MR formulation provides the appropriate PK characteristics to extend plasma concentration into the middle of the night (3–6 h postdose), while retaining the same tmax and terminal half‐life. Clinical Pharmacology & Therapeutics (2005) 77, P44–P44; doi:

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.