Comparative Bioavailability and Tolerability of a Single 2-mg Dose of 2 Repaglinide Tablet Formulations in Fasting, Healthy Chinese Male Volunteers: An Open-Label, Randomized-Sequence, 2-Period Crossover Study()

BACKGROUND: Repaglinide, an oral insulin secretagogue, was the first meglitinide analogue to be approved for use in patients with type 2 diabetes mellitus. OBJECTIVE: In our study, the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of repaglinide 2 mg were compared in a fasting, healthy Chinese male population. METHODS: This 2-week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in 22 healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 2-mg dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. After an overnight fast, subjects received a single oral dose of repaglinide (2 mg). Blood samples were drawn at predetermined time points (0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, and 6.0 hours). All plasma concentrations of repaglinide were measured by LC-MS/MS. The observed C(max), T(max), t(1/2), and AUC were assessed. The formulations were to be considered bioequivalent if the ln-transformed ratios of C(max) and AUC were within the predetermined bioequivalence range of 80% to 125% established by the State Food and Drug Administration of the People’s Republic of China. Tolerability was assessed throughout the study via subject interview, vital signs, and blood sampling. RESULTS: The mean (SD) age of the subjects was 24.2 (2.3) years; their mean (SD) weight was 62.6 (5.8) kg, their mean (SD) height was 172 (5.7) cm, and their mean (SD) body mass index was 21.0 (1.1). The mean (SD) C(max) for repaglinide with the test and reference formulations were 20.0 (5.1) and 18.7 (8.7) ng/mL. The AUC(0–t) for the test formulation was 46.3 (15.1) and AUC(0–∞) was 47.9 (16.5) ng(•)h/mL. With the reference formulation, the corresponding values were 46.4 (26.1) and 49.0 (31.3) ng(•)h/mL. The mean (SD) T(max) values with the test and reference formulations were 1.2 (0.7) hours and 1.5 (0.8) hours and the mean (SD) values t(1/2) values were 1.0 (0.3), and 0.9 (0.3) hours, respectively. The ln-transformed ratios of C(max), AUC(0–t), and AUC(0–∞) were 113.6:1, 105.6:1, and 104.7:1. The corresponding 90% CIs were 99.8 to 129.2, 93.4 to 119.5, and 91.8 to 119.5, respectively. CONCLUSIONS: This single-dose study found that the test and reference formulations of repaglinide met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated. ClinicalTrials.gov identifier: 2012L01684.