Bioequivalence of Fixed-Dose Repaglinide/Metformin Combination Tablet and Equivalent Doses of Repaglinide and Metformin Tablet: A Randomized, Single-Dose, Two-Period, Two-Sequence Crossover Study in Healthy Korean Male Volunteers

Abstract

T aim of this study was to evaluate the bioequivalence of a fixed-dose repaglinide/metformin combination (FDC) tablet at a dose of 2/500 mg with co-administration of equivalent doses of repaglinide (2 mg) and metformin (500 mg) as individual (EDI) tablets in healthy Korean male volunteers.This study was conducted as an open-label, randomized, single-dose, 2-period 2-squence crossover design in 48 healthy Korean male volunteers who received an FDC tablet or EDI tablets after a 12-hour overnight fast in each period. Plasma concentrations of repaglinide and metformin up to 24 hours were determined using a UPLC-MS/MS method. The pharmacokinetic parameters such as AUC0-t, AUC0-∞, Cmax, Tmax and t1/2, were analyzed. Analysis of variance was carried out using logarithmically transformed AUC0-t, AUC0-∞ and Cmax. The formulations were considered bioequivalent if the log-transformed ratios of AUC0–t, AUC0–∞, and Cmax were within the predetermined bioequivalence range (80-125%) established by the US Food and Drug Administration. Tolerability was assessed throughout the study. No significant sequence effect was detected. The point estimates (90% CIs) for AUC0-t, AUC0-∞ and Cmax based on EDI tablets were 1.101 (1.023-1.185), 1.099 (1.022-1.184) and 1.126 (1.015-1.249) for repaglinide, and 0.952 (0.896-1.011), 0.950 (0.897-1.007) and 0.984 (0.927-1.045) for metformin, respectively, satisfying the bioequivalence criteria of 80-125% as proposed by the US FDA. This single-dose study found that both Repaglinide and Metformin in a fixed-dose combination tablet were bioequivalent to individual tablets of repaglinide 2 mg and metformin 500 mg in these fasting, healthy Korean male volunteers.