Bioequivalence Evaluation of Immediate-Release Empagliflozin/Metformin Fixed-Dose Combination Tablets Under Fed Conditions in Healthy Mexican Subjects and Exploratory Analysis of Metformin Dose Proportionality

Background/Objectives: Fixed-dose combinations (FDCs) improve therapeutic adherence in type 2 diabetes. These studies aimed to evaluate the pharmacokinetics and establish the bioequivalence of four immediate-release empagliflozin/metformin FDC formulations under fed conditions in healthy Mexican subjects. Methods: A total of 42 healthy volunteers per study (168 total) were enrolled in four randomized, open-label, two-way crossover, single-dose studies with a 14-day washout period. Formulations were administered orally under standardized fed conditions. Plasma concentrations of both drugs were quantified using a validated liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) method. Results: Across all dose strengths, the 90% confidence intervals (CIs) for the geometric mean ratios of peak plasma concentration (Cmax) and area under the concentration–time curve (AUC0-t) for both empagliflozin and metformin were entirely within the 80.00–125.00% bioequivalence acceptance range. The specific 90% CIs for Cmax and AUC0-t were: Study A (5/850 mg): empagliflozin (90.18–103.16%; 94.37–101.81%), metformin (98.43–107.69%; 97.18–106.62%); Study B (12.5/500 mg): empagliflozin (91.94–102.77%; 93.38–98.51%), metformin (92.58–101.73%; 94.85–103.91%); Study C (12.5/850 mg): empagliflozin (95.47–107.74%; 95.34–101.25%), metformin (94.19–103.59%; 94.06–103.21%); and Study D (12.5/1000 mg): empagliflozin (94.53–107.10%; 98.13–105.66%), metformin (98.89–107.51%; 99.25–109.92%). Regarding safety, no serious adverse events occurred, and all reported events were mild or moderate and resolved completely. Conclusions: All evaluated empagliflozin/metformin FDCs successfully demonstrated bioequivalence and a favorable safety profile under fed conditions. These findings fulfill regulatory requirements and support their therapeutic interchangeability in clinical practice. An exploratory power-model analysis indicated a modest trend toward less-than-dose-proportional metformin exposure across the 500–1000 mg range (slope β ≈ 0.77–0.78). NCT07633015, NCT07633054, NCT07633028, and NCT07633041.