In vitro study of the drug–drug interaction potential of cetagliptin and clinical study of pharmacokinetic interaction of cetagliptin and metformin in healthy volunteers

Abstract

1. Cetagliptin is an oral, potent, and newly developed selective inhibitor of dipeptidyl peptidase-4 (DPP-4). We evaluated the in vitro drug–drug interaction (DDI) potential of cetagliptin, as well as the pharmacokinetics of cetagliptin and metformin and the interaction between cetagliptin and metformin.

2. Cetagliptin did not inhibit CYP1A2, CYP2C8, CYP2B6, CYP2C9, CYP2C19, and CYP3A4, only has a moderate inhibitory effect on CYP2D6, and did not induce CYP1A2, CYP2B6, and CYP3A4. Plasma protein binding of cetagliptin didn’t have species differences or concentration dependence. Cetagliptin was a substrate for P-glycoprotein (P-gp).

3. The 34 healthy subjects enrolled were randomly divided into two sequences (A and B) with 17 subjects in each sequence. Coadministration with metformin had no effect on cetagliptin AUC_0–120 (GMR, 99.25%; 90% CI, 95.96%–102.65%). There was a slightly increase in cetagliptin C_max (GMR, 117.33%; 90% CI, 102.54%–134.25%). Coadministration with cetagliptin did not affect the metformin’s AUC_0–24 (GMR, 108.54%; 90% CI, 101.41%–116.17%) or C_max (GMR, 97.67%; 90% CI, 90.96%–104.89%).

4. Based on in vitro study results, cetagliptin is unlikely to cause CYP-mediated, clinically relevant DDI. Although the possibility of transporter-mediated, clinically relevant DDI cannot be ruled out, there is little or no risk of side effects. Coadministration of cetagliptin and metformin had no clinically meaningful effect on the pharmacokinetics of each drug. There was no drug–drug interaction between cetagliptin and metformin. Both monotherapies and combination therapy were well tolerated. No serious AEs and hypoglycaemia was reported.

Keywords:

• Cetagliptin cytochrome P450 transporter drug–drug interaction pharmacokinetic metformin DPP-4 inhibitor

Disclosure statement

The authors were fully responsible for all content and editorial decisions, they were involved at all stages of manuscript development, and have approved the final version. All authors have no conflicts of interest to disclose.

Additional information

Funding

This study was sponsored by CGeneTech (Suzhou, China) Co., Ltd. The work is supported by national science and technology major project for significant new drug development funding project (2018ZX09301007-001).