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

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 AUC 0–8 h , AUC 0–12 h, C SS (max) , Ae 0–8 h and Ratio 0–8 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 AUEC 0–4 h , AUEC 0–0.5 h , and EC max 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 C ss (max) were 1.12 (1.072, 1.169) and 1.14 (1.057, 1.220), and AUEC 0–168 h , EC max , and EC min 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.