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Synergism in Pharmacokinetics of Retagliptin and Metformin Observed during Clinical Trials of their Combination Therapy Yong, Xiaolan; Hu, Tingting; Feng, Shiyin; Du, Xiaolin; Shi, Huiqing & Feng, Wang Abstract 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 (AUCinf) and the maximum observed plasma concentration (Cmax) 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 AUCinf and Cmax of retagliptin co-administered with metformin were 16.49 and 25.88 % higher than for retagliptin alone, respectively, while the AUCinf of metformin co-administered with retagliptin was 22.06 % higher than for metformin alone. The 90 % confidence interval of both glucose-lowering drugs’ AUCinf and Cmax 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. Keywords Retagliptin; Metformin; Pharmacokinetic interaction; Synergism; Type 2 diabetes

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