Comparative Bioavailability of Metformin Hydrochloride Oral Solution Versus Metformin Hydrochloride Tablets in Fasting Mexican Healthy Volunteers

Abstract

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 (AUC_0–t), the area under the concentration–time curve extrapolated to infinite time (AUC_0–∞), and the maximum plasma concentration (C_max) 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 AUC_0–t and C_max 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 AUC_0–t, AUC_0–∞ and C_max 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

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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.

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