Background: Metformin HCl 500 mg, prolonged‑release (test product) was developed as an alternative formulation to the reference product Metformin hydrochloride XR 500 mg. The objective of this study was to assess comparable bioavailability between them under fed conditions and to evaluate whether observed PK differences are likely to be clinically relevant for glycaemic control (Bailey 2024; Chitnis et al. 2016; Stage et al. 2015).

Methods: Open‑label, randomized, single‑dose, two‑treatment, four‑sequence, four‑period crossover in 24 healthy adult volunteers. Primary PK endpoints were Cmax and AUC (AUC0‑t, AUC0‑∞). Analyses included standard BE testing and a compartmental PK analysis with trial‑informed PK/PD simulations to project effects on fasting plasma glucose and HbA1c (simulation work by J. Schaap / PD‑Value). We applied a “comparable bioavailability” framework (B. Tuck) to interpret PK differences alongside bibliographic evidence.

Results: Cmax met conventional bioequivalence criteria in both fed and fasting conditions. AUC was shown not to be bioequivalent for the proposed product and the reference product (RP), but the difference in AUC between the test and the reference product based on bibliographic data is concluded not to lead to differences in safety and efficacy that are considered to be clinically relevant as compartmental modelling and multiple‑dose simulations predicted overlapping glycaemic outcomes for test and reference.

Conclusions: Cmax for test product meets bioequivalence criteria. Although single‑dose AUC values are lower for test product compared with reference product, bibliographic evidence together with PK/PD simulations indicates that these AUC differences are not considered clinically relevant for glycaemic control. Taken together, the data support a claim of comparable bioavailability for Metformin hydrochloride 500 mg, prolonged release granules versus Metformin hydrochloride XR 500 mg, extended release tablets.

Key references: Bailey CJ 2024; Chitnis S et al. 2016; Stage TB et al. 2015; Clinical study report 087‑23 (Clinical Overview, Metformin HCl prolonged‑release granules, June 2025); PD-value 2025.

Authors: O.W.F. Natan, J. Eliassen Schaap, B. Tuck, A. Franken, K.P. Bouter.