Bioequivalence Study of Two Tablet Formulations of Clonazepam 2 mg: A Randomized, Open-Label, Crossover Study in Healthy Mexican Volunteers Under Fasting Conditions

Neurol Ther. 2024 Feb;13(1):141-152. doi: 10.1007/s40120-023-00567-5. Epub 2023 Dec 2.

Abstract

Introduction: The prevalence of neurological disorders is high among the Mexican population. Clonazepam is primarily indicated to treat panic disorders, certain kinds of epilepsy such as status epilepticus, childhood motor seizures (petit mal absence, Lennox-Gastaut syndrome, and infantile spasms), anxiety, and muscle spasm. This study was performed to compare bioequivalence between two oral tablet formulations of clonazepam 2 mg in healthy Mexican volunteers under fasting conditions.

Methods: This phase I, randomized, open-label, two-treatment, crossover study included 30 healthy volunteers. Subjects were randomly assigned to either test or reference formulation of clonazepam 2 mg. Each study period was separated by 21-day washout period. Blood samples were collected at pre-dose and up to 72 h after drug administration. Clonazepam concentrations were determined using a validated ultra-flow liquid chromatography-tandem mass spectrometric method. Pharmacokinetic parameters were determined using a non-compartmental method. Two formulations were considered bioequivalent if geometric mean ratios (test/reference) were between 80% and 125%. Safety was evaluated by recording adverse events.

Results: Pharmacokinetic parameters were comparable between test and reference formulations. The mean maximum plasma concentration (Cmax) was ≈ 13 ng/mL, area under the plasma concentration-time curve from time 0 to last measurable concentration (AUC0-t) was ≈ 360 ng h/mL, time to reach maximum plasma concentration (Tmax) was ≈ 3 h, and elimination half-life (t1/2) was ≈ 43 h. Geometric mean ratios (90% confidence interval) of Cmax (99.2-115.3%), AUC0-t (100.6-110.6%), and AUC0-∞ (98.5-111.6%) were within the bioequivalence range. Seven non-serious adverse events (mostly asymptomatic hypotension) were recorded.

Conclusion: The test and reference formulations of clonazepam 2 mg were bioequivalent and well tolerated in healthy Mexican volunteers under fasting conditions.

Protocol authorization number: 213301410B0051 (Approved on April 13, 2021).

Keywords: Clonazepam; Crossover study; Epilepsy; Fasting; Pharmacokinetics; Safety.