Bioequivalence and Pharmacokinetic Evaluation of Two Tablet Formulations of Carvedilol 25-mg: A Single-Dose, Randomized-Sequence, Open-Label, Two-Way Crossover Study in Healthy Chinese Male Volunteers

Abstract

Background:

Carvedilol is a nonselective-blocking agent and is used in the treatment of hypertension and angina pectoris.

Objective:

The aim of this study was to evaluate bioequivalence of two 25-mg tablet formulations of carvedilol following single oral dose in adult male volunteers.

Methods:

This was a randomized, single-dose, open-label, crossover bioequivalence study. Plasma samples were collected before dosing and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12 and 24 h after dosing. Plasma concentrations of Carvedilol were determined by using a validated LC-MS/MS method. Statistical analysis of the pharmacokinetic parameters C_max, AUC_0–24, and AUC_0–∞ was conducted to determine bioequivalence.

Results:

23 healthy male Chinese volunteers were enrolled in the study. The mean (SD) C_max, AUC_0–24, and AUC_0–∞ values after administration of the test and reference formulations, respectively, were as follows: 73.71 (34.04) vs. 78.93 (43.64) ng/mL, 285.1 (147.0) vs. 296.9 (176.1) ng/mL · h, and 296.5 (161.4) vs. 303.4 (177.9) ng/mL · h. The 90% CIs of the ratios (test vs. reference) for the ln-transformed C_max, AUC_0–24, and AUC_{0 − ∞} were 85.3% to 114.3%, 90.4% to 107.6%, and 90.9% to108.4%, respectively, meeting the criteria of SFDA, FDA and EMEA for bioequivalence. The relative bioavailability of the test formulation to reference formulation was 100.1%. Both formulations were generally well tolerated and no serious AEs were reported in the study.

Conclusions:

The 90% CIs for the ratios of mean C_max, AUC_0–24, and AUC_0–∞ met the regulatory criteria for bioequivalence.

Key words

carvedilol - bioequivalence - pharmacokinetics - liquid chromatography tandem mass spectrometry - LC-MS/MS

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