Characterization of Extended-Release Lorazepam: Pharmacokinetic Results Across Phase 1 Clinical Studies

Authors

Sanjay J Mathew
Shedly Jean-Lys
Rupinder Phull
Rama Yarasani

Language

English

Publication Date

7-1-2023

Journal

Journal of Clinical Psychopharmacology

DOI

10.1097/JCP.0000000000001715

PMID

37335199

PMCID

PMC10309101

PubMedCentral® Posted Date

6-19-2023

PubMedCentral® Full Text Version

Post-print

Abstract

Purpose/background: Once-daily extended-release (ER) lorazepam was developed to reduce fluctuations in plasma levels compared with lorazepam immediate-release (IR) for short-term anxiety relief. Here we report a series of phase 1 randomized, open-label, multiperiod crossover studies characterizing ER lorazepam pharmacokinetics and safety in healthy adults.

Methods/procedures: These phase 1 studies assessed the pharmacokinetics of ER lorazepam administered: (study 1) 3 mg once daily versus IR lorazepam 1 mg 3 times a day (TID; every 8 hours), (study 2) with or without food, and (study 3) intact versus sprinkled onto food. Study 3 further evaluated the proportionality of 1 × 4- versus 4 × 1-mg doses. Safety was also monitored.

Findings/results: There were 43, 27, and 29 subjects who completed studies 1, 2, and 3, respectively. The 90% confidence intervals for Cmax,SS , Cmin , and AUC TAU,SS of once-daily ER lorazepam compared with IR given TID were within 80% to 125% limits establishing steady-state bioequivalence. Maximum mean lorazepam concentrations were achieved at 11 hours compared with 1 hour after dosing for ER versus IR lorazepam, respectively. Pharmacokinetic parameters ( Cmax , AUC last or AUC 0- t , AUC inf or AUC 0-inf ) of ER lorazepam were bioequivalent whether taken with or without food, administered intact or sprinkled onto food, or administered as intact 1 × 4- versus 4 × 1-mg capsules. No serious safety concerns were found.

Implications/conclusions: Once-daily ER lorazepam provided a pharmacokinetic profile bioequivalent to IR lorazepam given TID and was well tolerated in healthy adults across all phase 1 studies. These data suggest that ER lorazepam could be an alternative for patients currently treated with IR lorazepam.

Keywords

Adult, Humans, Lorazepam, Delayed-Action Preparations, Cross-Over Studies, Area Under Curve

Published Open-Access

yes

Recommended Citation

Mathew, Sanjay J; Jean-Lys, Shedly; Phull, Rupinder; et al., "Characterization of Extended-Release Lorazepam: Pharmacokinetic Results Across Phase 1 Clinical Studies" (2023). Staff and Researcher Publications. 46.
https://digitalcommons.library.tmc.edu/clinic_pub/46