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

Abstract: Lorazepam is an allosteric GABA-receptor modulator approved for the treatment of anxiety and primarily administered as immediate-release tablets. The current immediate-release formulation is conventionally given in doses ranging from 1-10-mg/day, two or three times a day. An extended-release, once-daily formulation has been developed to provide more consistent intra-day levels of lorazepam. Here we report the results of a Phase 1, randomized, open-label, two-treatment, multiple-dose crossover study comparing the steady-state bioavailability and safety of once-daily extended-release lorazepam (3-mg) to immediate-release lorazepam (1-mg) given thrice daily (q8h) in healthy adults for 7 consecutive days per period. 46 subjects were enrolled and randomized (23/arm), with 43 subjects completing both periods and included in the pharmacokinetic analysis. Mean lorazepam concentrations were found to be similar across a 24-hour sampling interval, with maximum mean concentrations achieved at 11 hours post-dose for the extended-release (33.02 ± 9.83 ng/mL) and at 1-hour post-dose for the immediate-release formulation (39.30 ± 12.69 ng/mL). The immediate-release formulation exhibited three peaks in lorazepam concentrations, corresponding to each q8h dose. Mean pharmacokinetic parameters were similar between extended-release and immediate-release formulations. The Cmax,ss, Cmin,ss, and AUCTAU ratio and 90% CI achieved with extended-release lorazepam were within bioequivalence limits of 80-125% compared to the immediate-release formulation. Extended-release lorazepam was well-tolerated, with the most frequently reported adverse events being constipation (n=19 events in 12 subjects overall) and headache (n=9 events in 7 subjects overall). The data suggest that once-daily 3-mg extended-release lorazepam is well-tolerated and is bioequivalent to 1-mg immediate-release lorazepam administered every eight hours.Short Description: Results of a Phase 1, randomized, open-label, 2-treatment, multiple-dose crossover study are discussed comparing the steady-state bioavailability and safety of once-daily extended-release lorazepam (3-mg) to immediate-release lorazepam (1-mg) given thrice daily (q8h) in healthy adults. Data suggest once-daily 3-mg extended-release lorazepam being well-tolerated and bioequivalent to 1-mg immediate-release lorazepam administered every 8 hours.Name of Sponsoring Organization(s): Almatica Pharma LLC, managed by Alvogen PB Research & Development LLC; subsidiaries of Alvogen Pharma US, Inc.