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.

摘要

1. Cetagliptin 是一种口服、强效、新开发的二肽基肽酶-4 (DPP-4) 选择性抑制剂。我们评估了西格列汀的体外药物相互作用 (DDI) 潜力，以及西格列汀和二甲双胍的药代动力学以及西格列汀和二甲双胍之间的相互作用。

2. 西格列汀不抑制CYP1A2、CYP2C8、CYP2B6、CYP2C9、CYP2C19和CYP3A4，仅对CYP2D6有中度抑制作用，不诱导CYP1A2、CYP2B6和CYP3A4。西格列汀与血浆蛋白结合不存在种属差异或浓度依赖性。西格列汀是 P-糖蛋白 (P-gp) 的底物。

3. 将纳入的 34 名健康受试者随机分为两个序列（A 和 B），每个序列 17 名受试者。与二甲双胍合用对西格列汀 AUC _0–120没有影响（GMR，99.25%；90% CI，95.96%–102.65%）。西格列汀C _max略有增加（GMR，117.33%；90% CI，102.54%–134.25%）。合用cetagliptin并不影响二甲双胍的AUC _0-24（GMR，108.54％; 90％CI，101.41％-116.17％）或Ç_最大（GMR，97.67％; 90％CI，90.96％-104.89％）。

4. 根据体外研究结果，西格列汀不太可能引起 CYP 介导的临床相关 DDI。尽管不能排除转运蛋白介导的临床相关 DDI 的可能性，但副作用风险很小或没有。西格列汀和二甲双胍合用对每种药物的药代动力学没有临床意义的影响。西格列汀和二甲双胍之间没有药物相互作用。单一疗法和联合疗法均具有良好的耐受性。没有报告严重的 AE 和低血糖。