Synergism in Pharmacokinetics of Retagliptin and Metformin Observed during Clinical Trials of their Combination Therapy

Purpose: To investigate the safety and potential pharmacokinetic (PK) interaction between retagliptin, a selective inhibitor of dipeptidyl peptidase-4, and metformin in healthy subjects. Methods: In open-label, randomized, three-period, three-treatment crossover studies, 15 subjects received 100 mg retagliptin, 1500 mg metformin or the combination. The area under the curve from the time of dosing to infinity (AUC inf ) and the maximum observed plasma concentration (C max ) of each drug were measured. Results: The combination of retagliptin and metformin did not result in clinically significant alterations in the pharmacokinetics of SP2086 or metformin. The AUC inf and C max of retagliptin co-administered with metformin were 16.49 and 25.88 % higher than for retagliptin alone, respectively, while the AUC inf of metformin co-administered with retagliptin was 22.06 % higher than for metformin alone. The 90 % confidence interval of both glucose-lowering drugs’ AUC inf and C max of the geometric mean ratios of SP2086 + metformin fell within the pre-specified interval of 80 - 125 %. No laboratory adverse conditions occurred during the study. Retagliptin appeared generally safe and well-tolerated when administered alone or in combination with metformin. Conclusion: The results may be an indication that no dose adjustments are likely to be required when retagliptin is given in combination with metformin.