Investigation of Potential Pharmacokinetic Interactions Between Teneligliptin and Metformin in Steady-state Conditions in Healthy Adults

Purpose: We assessed the effects of coadministration of metformin and teneligliptin on their pharmacokinetics in steady-state conditions relative to the administration of either drug alone. Methods: This was a Phase I, single-center, open-label, 2-way parallel-group study in healthy male and female subjects. Subjects in group 1 (n = 20) were administered 40 mg of teneligliptin once daily for 5 days, and 850 mg of metformin BID was added to ongoing teneligliptin for an additional 3 days. The subjects in group 2 (n = 20) were administered 850 mg of metformin BID for 3 days, and 40 mg of teneligliptin once daily was added to ongoing metformin for an additional 5 days. Pharmacokinetic outcomes were the AUC(0-tau) and G(max) of metformin and teneligliptin when administered alone or in combination. Findings: Ten male and 10 female subjects participated in each group (mean +/- SD age 39.2 +/- 11.6 years [range, 19-63 years] in group 1, 47.6 +/- 11.9 years [27-64] in group 2; mean SD BMI 23.36 +/- 2.45 in group 1, 24.56 +/- 2.54 in group 2). One female subject in each group was withdrawn because of an adverse event (AE) (vomiting). All 20 subjects in each group were included in the safety analyses, and 19 subjects in each group were included in the pharmacokinetic analyses. The geometric least square means ratio (teneligliptin plus metformin/teneligliptin alone) for G(max) and the AUC(0-tau) for teneligliptin were 0.907 (90% CI, 0.853-0.965) and 1.042 (90% CI, 0.997-1.089), respectively. The geometric least square means ratio (metformin plus teneligliptin/metformin alone) for the G(max) and AUC(0-tau) for metformin were 1.057 (90% CI, 0.974-1.148) and 1.209 (90% CI, 1.143-1.278). The 90% CIs were within the prespecified threshold for equivalence (0.80-1.25), except for the AUC(0-tau) for metformin, which was increased by teneligliptin by 20% relative to metformin alone. In group 1, nine subjects experienced 25 AEs during treatment with teneligliptin alone and 10 subjects experienced 15 AEs during treatment with teneligliptin plus metformin. In group 2, eight subjects experienced 11 AEs during treatment with metformin alone and 11 subjects experienced 18 AEs during treatment with metformin plus teneligliptin. Two AEs in each treatment group were rated as severe. Results of in vitro experiments suggest that teneligliptin-mediated inhibition of organic cation transporter-2 does not increase metformin exposure. (C) 2015 Elsevier HS Journals, Inc. All rights reserved.