Effect of Food on Pharmacokinetics of Once-Daily Extended-Release Lorazepam

Abstract: Lorazepam is an allosteric GABA-receptor modulator approved for the treatment of anxiety disorders. Traditionally, it is administered as immediate-release tablets given two or three times daily for short-term anxiety relief, in doses ranging from 1-10-mg/day. Extended-release lorazepam is a once-daily formulation developed to administer more consistent drug levels. An important characteristic of an anxiolytic is the flexibility of being administered with or without food. Here we report the results of a Phase 1, randomized, open-label, two-sequence, two-period crossover study evaluating the effect of food on bioavailability of once-daily extended-release lorazepam in healthy adults. 28 subjects were randomized to receive two separate administrations of once-daily extended-release lorazepam (4-mg) under both fasting and fed conditions (14 subjects per sequence), separated by a 10-day washout. 27 subjects completed both study periods. Extended-release lorazepam administered with food delayed the median Tmax by ~2 hours, with mean pharmacokinetic parameters otherwise similar under fasted and fed conditions: Cmax was 19.20 and 19.58 ng/mL; AUClast was 898.97 and 866.65 hr*ng/mL, and t1/2 was 17.59 and 17.38 hours, respectively. The Cmax, AUCinf, and AUClast under fasted and fed conditions were within bioequivalency limits of 80-125% (geometric mean ratios of 103.85% [98.35-109.66 90% CI], 96.82% [93.63-100.11 90% CI], and 96.97% [93.99-100.05 90% CI], respectively). Extended-release lorazepam given with food was well tolerated, with the most frequently reported adverse events being headache (n=2, 1 subject per condition) and somnolence (n=2, both under fasting conditions). Collectively, these data suggest there is no impact of food on the bioavailability of extended-release lorazepam.Short Description: Results of a Phase 1, randomized, open-label, 2-sequence, 2-period crossover study are reported evaluating the effect of food on bioavailability of once-daily extended-release lorazepam in healthy adults. Data support no impact of food on the bioavailability of extended-release lorazepam.Name of Sponsoring Organization(s): Almatica Pharma LLC, managed by Alvogen PB Research & Development LLC; subsidiaries of Alvogen Pharma US, Inc.