RESUMO
INTRODUCTION: Metformin tablets may be challenging to swallow not only for those patients with dysphagia but also for children and the elderly. A metformin solution was developed for easier administration and flexible dose adjustment mantained with the same bioavailability of tablets. The objective of this study was to assess the single-dose oral bioavailability of metformin hydrochloride administered as an oral solution (500 mg/5 mL) compared with metformin hydrochloride 500 mg tablets in fasting Mexican healthy volunteers. METHODS: A randomized, single dose, two-period, two-sequence, crossover study design with a 7-day washout interval was conducted. Subjects were randomly assigned to receive a single dose of 500 mg metformin hydrochloride, either as an oral solution (test drug) or as a tablet (reference drug), after 10 h of fasting. Plasma samples (16) were collected over a 16-h period after drug administration. Bioequivalence was declared when the ratio for the 90% confidence intervals (CI) of the difference in the means of the log-transformed area under the concentration-time curve from time 0 to the last observed concentration time (AUC0-t), the area under the concentration-time curve extrapolated to infinite time (AUC0-∞), and the maximum plasma concentration (Cmax) of the two products were within 0.80 and 1.25 interval. Plasma concentrations were analyzed using reverse phase chromatography by tandem mass spectrometry (LC-MS/MS). Safety and tolerability of metformin were also assessed in all subjects. RESULTS: 24 subjects were enrolled and completed the study (15 female and 9 male). Test and reference metformin hydrochloride were bioequivalent during the extent of exposure since AUC0-t and Cmax 90% CIs corresponded to 89.77-101.08% and 89.63-102.48%, respectively, both being within the pre-specified acceptance range criteria (80-125%). There were two adverse events (AE) with the reference formulation that were not related to the study drug. CONCLUSIONS: Bioequivalence in healthy volunteers in fasting conditions of the two metformin hydrochloride formulations (oral solution and tablets) was established, being the difference in means of AUC0-t, AUC0-∞ and Cmax within the acceptance range (80-125%). Oral solution formulation could offer the advantages of allowing adjusted doses and easier swallowing for every patient. Plain language summary is available for this article. TRIAL REGISTRATION: National Clinical Trials Registry (RNEC by its Spanish acronym), BD METF-Sil No. 86-15. Mexican Medicine Agency (COFEPRIS) Registry: 153300410B0368. FUNDING: Laboratorios Silanes, S.A. de C.V.
