Pharmacokinetics of a fixed-dose combination of mitiglinide and metformin versus concurrent administration of individual formulations in healthy subjects: A randomized, open-label, two-treatment, two-period, two-sequence, single-dose, crossover study

Background: In the treatment of diabetes mellitus, combined drugs with different mechanisms of action can be effective when adequate glycaemic control is difficult with monotherapy. A fixed-dose combination (FDC) tablet of mitiglinide and metformin has been developed as a second-line treatment for type 2 diabetes. Objectives: The objective of this study was to compare the pharmacokinetics and safety of a FDC and a free combination of mitiglinide and metformin in healthy male subjects. Methods: A randomized, open-label, two-period, two-treatment, single-dose, crossover study was conducted in 24 healthy Korean male subjects. In one period, a FDC tablet of mitiglinide and metformin (10 mg/500 mg) was administered, and in the other period, corresponding doses of individual formulations were administered. Results: Twenty-four subjects were enrolled and 19 subjects completed the study. The geometric mean ratios (90 % confidence interval) of the maximum plasma concentration (C_max) and area under the plasma concentration-time curve from time zero to the time of the last measurable concentration (AUC _last) were 0.9694 (0.8120, 1.1573) and 0.8951 (0.8440, 0.9494) for mitiglinide, and 1.0235 (0.9373, 1.1057) and 1.0542 (0.9697, 1.1460) for metformin, which were within the bioequivalence range. Among the 23 subjects who received study drugs, 15 subjects experienced 34 adverse events (AEs). The most frequently reported AEs were feeling hot and compensatory sweating. There were no serious AEs and no significant differences in the incidence of AEs between the two treatments. Conclusion: A FDC tablet of mitiglinide and metformin was generally well tolerated in healthy male subjects. Administration of a FDC tablet and concomitant administration of individual formulations did not show significantly different pharmacokinetic profiles.