Bioequivalence of sitagliptin/metformin fixed-dose combination tablets and concomitant administration of sitagliptin and metformin in healthy adult subjects: a randomized, open-label, crossover study.

Background: Treatment with an oral antihyperglycaemic agent administered as monotherapy is often unsuccessful at achieving or maintaining glycaemic control in patients with type 2 diabetes mellitus. The combined use of sitagliptin and metformin is an effective treatment for type 2 diabetes mellitus, consistent with the complementary mechanisms of action by which these two agents improve glucose control. Objectives: To establish bioequivalence between sitagliptin/metformin fixeddose combination (FDC) tablets (Janumet®) and co-administration of corresponding doses of sitagliptin and metformin as individual tablets. Methods: This was an randomized, open-label, two-part, two-period crossover study, which included a total of 48 healthy subjects, 24 subjects per part (parts I and II). Within each part, subjects were assigned to receive treatments in random order; treatment periods were separated by a washout interval of at least 7 days. Eligible study participants included healthy, non-smoking (within previous 6 months), male and female subjects aged between 18 and 45 years with a body mass index ≤32kg/m2. Part I consisted of treatments A (co-administration of sitagliptin 50 mg and metformin 500 mg) and B (sitagliptin/metformin 50mg/500mg FDC tablet); part II consisted of treatments C (co-administration of sitagliptin 50 mg and metformin 1000 mg) and D (sitagliptin 50 mg/metformin 1000 mg FDC tablet). Blood samples were collected pre-dose and up to 72 hours post-dose in each treatment period for determination of plasma sitagliptin and metformin concentrations and calculation of the respective pharmacokinetic parameters. The area under the plasma concentration-time curve from time zero to infinity (AUC∞) and the maximum plasma concentration (Cmax) for both sitagliptin and metformin were designated as the primary and secondary study endpoints, respectively, and analysed using an ANOVA model after logarithmic transformation of the data. Bioequivalence was established if the 90% confidence intervals (CIs) for the geometric mean ratios (GMRs; FDC tablet/co-administration) of the AUC∞ and Cmax for both sitagliptin and metformin fell within pre-specified bounds of (0.80, 1.25). Results: The GMRs (90% CI) for the AUC∞ of sitagliptin 50 mg and metformin 500 mg were 0.98 (0.96, 1.00) and 1.0 (0.95, 1.04), respectively, and for Cmax of sitagliptin and metformin were 1.00 (0.94, 1.06) and 1.00 (0.94, 1.06), respectively. The GMRs (90% CI) for the AUC∞ of sitagliptin 50 mg and metformin 1000 mg (part II) were 0.97 (0.95, 0.99) and 1.00 (0.94, 1.07), respectively, and for the Cmax of sitagliptin and metformin were 0.94 (0.88, 1.01) and 1.01 (0.93, 1.10), respectively. In both part I and part II, the 90% CIs of the GMRs of the AUC∞ and Cmax for both sitagliptin and metformin all fell within the pre-specified bioequivalence bounds of (0.80, 1.25). Administration of single doses of sitagliptin/metformin 50 mg/500 mg (part I) and 50 mg/1000 mg FDC tablets (part II) and co-administration of corresponding doses of sitagliptin and metformin as individual tablets were generally well tolerated. Conclusion: The sitagliptin/metformin 50 mg/500 mg and 50 mg/1000 mg FDC tablets are bioequivalent to co-administration of corresponding doses of sitagliptin and metformin as individual tablets and support bioequivalence to the sitagliptin/metformin 50 mg/850 mg tablet strength. These results indicate that the safety and efficacy profile of co-administration of sitagliptin and metformin can be extended to the sitagliptin/metformin FDC tablets.