Bioequivalence and safety evaluation of two preparations of metformin hydrochloride sustained-release tablets (Boke(®) and Glucophage(®)-XR) in healthy Chinese volunteers: a randomized phase I clinical trial

BACKGROUND: As per the National Medical Products Administration (NMPA) requirements, the quality and efficacy of generic drugs must be consistent with those of the innovator drug. We aimed to evaluate the bioequivalence and safety of generic metformin hydrochloride sustained-release (MH-SR) tablets (Boke(®)) developed by Beijing Wanhui Double-crane Pharmaceutical Co. Ltd., China and the innovator product metformin hydrochloride extended-release tablets (Glucophage(®)-XR) manufactured by Bristol-Myers Squibb Company, New York, NY, in healthy Chinese volunteers. MATERIALS AND METHODS: We performed a bioequivalence and safety assessment of MH-SR (500 mg/tablet) and Glucophage(®)-XR (500 mg/tablet) tablets in a randomized, open-label, two-period, two-sequence crossover, single-dose oral study in 48 healthy Chinese adult participants under fasting conditions (Chinese Clinical Trial Registration No. CTR20171306). The washout period was seven days. Bioequivalence (80.00–125.00%) was assessed using adjusted geometric mean ratios (GMRs) and two-sided 90% confidence intervals (CIs) of the area under the curve (AUC) and maximum concentration (C(max)) for each component. RESULTS: The 90% CIs of the test/reference preparation for key pharmacokinetic parameters were 97.36–108.30% for AUC(0→)(t), 97.26–108.09% for AUC(0→∞) and 96.76–111.37% for C(max). No severe adverse events (AEs) were observed. However, 38 adverse drug reactions (ADRs) occurred, including metabolic or nutritional conditions (n = 8), infections (n = 2), gastrointestinal conditions (n = 10) and abnormal inspection (n = 18). No significant difference was observed between MH-SR (23 ADRs, 10 participants) and Glucophage(®)-XR (15 ADRs, 12 participants) (p = .500). Bioequivalence was concluded since the 90% CIs of the main pharmacokinetic parameters were within the equivalence interval (80.00–125.00%). CONCLUSIONS: MH-SR (500 mg/tablet) and Glucophage(®)-XR (500 mg/tablet) were found to be bioequivalent and safe under fasting conditions in healthy Chinese participants. Thus, the market demand for MH-SR tablets (500 mg/tablet) can be met using the generic alternative. KEY MESSAGES: Generic MH-SR tablets (500 mg, Beijing Wanhui Double-crane Pharmaceutical Co. Ltd., Beijing, China) and innovator MH-SR tablets (Glucophage(®)-XR, 500 mg, Bristol-Myers Squibb Company, New York, NY, USA) were bioequivalent and safe in healthy Chinese volunteers under single-dose administration and fasting conditions. The main goal of this study is to support an increase in the supply of MH-SR tablets in China by proving the efficacy and safety of a generic alternative. Although no sugar was administered in the BE trial of the MH-SR tablets under fasting conditions, no hypoglycaemic event occurred. The method used in this study is expected to serve as a reference for BE studies of different MH-SR formulations.