Pharmacokinetic and Pharmacodynamic Drug‐Drug Interactions Between Cofrogliptin and Metformin in Healthy Subjects: A Single‐Center, Single‐Arm, Phase I Study in China

Abstract

Abstract This single‐center, single‐arm, Phase I study evaluated drug–drug interactions (DDIs) between cofrogliptin and metformin in healthy Chinese subjects. Twenty‐two subjects sequentially received metformin monotherapy (Days 1–4), cofrogliptin monotherapy (Days 6–34), and combination therapy (Days 38–47). Serial blood/urine samples were collected for pharmacokinetic (PK) and pharmacodynamic (PD) analyses. Cofrogliptin showed no significant impact on metformin's PK and PD properties: the geometric mean ratios (GMRs, metformin + cofrogliptin/metformin) with 90% confidence intervals (CIs) for metformin AUC0–8 h, AUC0–12 h, CSS (max), Ae0–8 h and Ratio0–8 h, were 0.872 (0.809, 0.941), 0.900 (0.834, 0.971), 0.840 (0.743, 0.950), 0.899 (0.782, 1.032), and 0.994 (0.871, 1.136), respectively; 90% CIs for plasma glucose AUEC0–4 h, AUEC0–0.5 h, and ECmax of combination (combination vs cofrogliptin monotherapy) all fell within 0.80–1.25. Metformin did not statistically affect cofrogliptin's PK and PD properties, as the GMRs (metformin + cofrogliptin/cofrogliptin) (90% CIs) for cofrogliptin AUC over the dosing interval and Css (max) were 1.12 (1.072, 1.169) and 1.14 (1.057, 1.220), and AUEC0–168 h, ECmax, and ECmin for dipeptidyl peptidase‐4 inhibition rate were 1.01 (1.003, 1.015), 1.00 (1.001, 1.009), and 1.03 (1.005, 1.040), respectively. No deaths, serious adverse events, or severe hypoglycemia occurred. In conclusion, the combination of cofrogliptin and metformin had no clinically significant PK or PD DDIs in healthy Chinese subjects.