Bioequivalence of Related GelShieldⓇ Sustained-release Formulations of Metformin: A Pooled Pharmacokinetic Analysis

Abstract

Purpose: Glucophage^Ⓡ (Merck Healthcare KGaA, Darmstadt, Germany) is the originator brand of metformin hydrochloride, an oral antidiabetic drug. Metformin is recommended in guidelines as first-line treatment of type 2 diabetes mellitus and increasingly in related insulin-resistant conditions, such as prediabetes and polycystic ovary syndrome. The GelShield^Ⓡ sustained-release formulation tablet of Glucophage^Ⓡ has been improved from the historic version marketed in 2000. Bioequivalence has been demonstrated stepwise along this evolution; however, a head-to-head evaluation between the initial and the current version is missing. This analysis aims to close this gap and to determine bioequivalence between related originator GelShield^Ⓡ sustained-release formulations of metformin, Glucophage^Ⓡ (GXR 500 mg), from Europe and the United States.

Methods: Data from seven randomized crossover bioequivalence studies in 361 healthy participants of Asian and non-Asian ethnicity from Europe, the United States, and Asia were considered. All evaluated a single oral dose of 500 mg of the test and reference formulation in healthy male and female participants in fed and fasted state. Bioequivalence was evaluated by means of a combined bridging analysis of available data on the current round tablet from Europe (rGXR EU) and the historic oblong tablet from the United States (oGXR US) in healthy Asian and non-Asian participants under fed and fasting conditions. Bioequivalence between the two formulations was assessed statistically with a mixed effects model for AUC_0-t, C_max, and AUC_0-inf.

Findings: In all studies, bioequivalence between the respective test and reference formulations of GXR was shown. Statistical analysis of pooled pharmacokinetic data of 2 (primary pooling set) or 3 studies (secondary pooling set) demonstrated bioequivalence between rGXR EU and oGXR US via bridging with oGXR EU. The 90% CI for the geometric mean ratio of all pharmacokinetic parameters was within the bioequivalence range of 0.80 to 1.25. In the primary pooling set, geometric least squares mean ratios in the fed group ranged from 0.9931 (90% CI, 0.9151-1.0778) for AUC_0-inf to 1.1344 (90% CI, 1.0711-1.2014) for C_max; results in the fasted group were similar. The secondary pooling set, which added a study in Asians, confirmed these findings.

Implications: Bioequivalence was determined between sustained-release formulations of Glucophage^Ⓡ from Europe and the United States under fasted and fed conditions in healthy men and women, including different ethnicities. The efficacy and safety of Glucophage^Ⓡ XR can be claimed along the evolution from oGXR US, via oGXR EU to rGXR EU, and in several ethnicities and production sites.

Keywords: Bioequivalence; Healthy volunteer; Indirect comparison; Metformin; Pharmacokinetic; Sustained release.