Bioequivalence of Once-Daily Extended-Release Lorazepam Compared to Twice-Daily Immediate-Release Lorazepam

Abstract: Lorazepam is an allosteric GABA-receptor modulator approved for the treatment of anxiety. The existing formulation delivers immediate-release lorazepam to provide short-term anxiety relief at doses ranging from 1-10-mg/day, given in tablets two to three times daily. An extended-release formulation has recently been developed to provide more consistent levels of lorazepam throughout the day compared to immediate-release dosing. Here we report the findings from a Phase 1, randomized, open-label, two-period, two-sequence, two-treatment, multiple-dose crossover study assessing the steady-state safety and relative bioavailability of once-daily, extended-release lorazepam in a 4-mg dose compared to immediate-release lorazepam administered twice daily (2-mg q12h) in healthy adults. 77 subjects were randomized to one of the two treatment sequences. Sixty-eight subjects completed both periods of the study, without a washout, and were included in the statistical analyses. The geometric mean ratios for Cmax,ss, Cmin,ss, and AUCTAU were 72.97% (70.56-75.47 CI; 27% lower for extended-release lorazepam), 88.90% (85.53-92.42 CI), and 84.53% (81.93-87.22 CI), respectively. Steady-state pharmacokinetic (PK) parameters were similar between formulations, with mean percent fluctuation and swing values lower for extended-release (4-mg; 38.6% and 0.491, respectively) compared to immediate-release lorazepam given q12h (59.6% and 0.817, respectively). The most frequently reported adverse events (AEs) overall were somnolence (75.3%), dizziness (16.9%), nausea (9.1%), gait disturbance (6.5%), and vomiting (5.2%); with more AEs following immediate-release lorazepam than with extended-release lorazepam. The data suggest that once-daily extended-release lorazepam (4-mg) is well-tolerated and achieves a similar PK profile with less fluctuation in mean plasma lorazepam levels compared to twice-daily 2-mg immediate-release lorazepam.Short Description: Findings are discussed from a Phase 1, randomized, open-label, 2-period, 2-sequence, 2-treatment, multiple-dose crossover study assessing the steady-state safety and relative bioavailability of once-daily, extended-release lorazepam in a 4-mg dose compared to immediate-release lorazepam administered twice daily (2-mg q12h) in healthy adults. The data support once-daily extended-release lorazepam (4 mg) being well-tolerated, with a similar PK profile and less fluctuation in mean plasma lorazepam levels compared to twice-daily 2-mg immediate-release lorazepam.Name of Sponsoring Organization(s): Almatica Pharma LLC, managed by Alvogen PB Research & Development LLC; subsidiaries of Alvogen Pharma US, Inc.