Dose Proportionality and the Effect of Sprinkling on the Bioavailability of Once-Daily Extended-Release Lorazepam

Abstract: Lorazepam, traditionally administered as immediate-release tablets, is an allosteric GABA-receptor modulator approved for the treatment of anxiety disorders. A once-daily, extended-release formulation of lorazepam capsules has been developed to deliver more consistent drug levels. However, some patients who have difficulty swallowing solid oral dosage formulations may require their medication sprinkled on food. Further, since extended-release lorazepam will be administered in doses ranging from 1–4-mg, the dose-normalized pharmacokinetic (PK) parameters of the lowest (1-mg) compared to the highest (4-mg) doses were evaluated for dose proportionality. Here we report the results of a Phase 1, randomized, open-label, three-period, six-sequence, three-treatment clinical study evaluating the bioavailability and safety of once-daily extended-release lorazepam. Subjects were randomized to receive either a single dose of extended-release lorazepam (4-mg) sprinkled on soft food, given as an intact capsule, or administered as four 1-mg intact capsules. There were 30 subjects included in the PK analysis, with 29 subjects completing all study periods. Pharmacokinetic parameters including Tmax, Cmax, AUC0-t, AUC0-inf, and t1/2 were found to be similar for 4-mg extended-release lorazepam given as a sprinkled capsule, intact, or as four 1-mg capsules; with the geometric means for Cmax, AUC0-t, and AUC0-inf all within the bioequivalence confidence limits of 80-125%. The most frequently reported adverse event was somnolence (16.7% of overall subjects, n=5). The data demonstrate that administering extended-release lorazepam as a sprinkled capsule does not impact its PK profile, and that once-daily 4-mg doses are bioequivalent to four 1-mg doses.Short Description: Findings are discussed from a Phase 1, randomized, open-label, 3-period, 6-sequence, 3-treatment clinical study evaluating the bioavailability and safety of once-daily extended-release lorazepam given as either a single 4-mg dose sprinkled on soft food, as an intact capsule, or administered as four 1-mg intact capsules. The data demonstrate that administering extended-release lorazepam as a sprinkled capsule does not impact its PK profile, and that once-daily 4-mg doses are bioequivalent to four 1-mg doses.Name of Sponsoring Organization(s): Almatica Pharma LLC, managed by Alvogen PB Research & Development LLC; subsidiaries of Alvogen Pharma US, Inc.