Objective: To evaluate the pharmacokinetic (PK) parameters of ripretinib and its active metabolite in Chinese patients with gastrointestinal stromal tumor (GIST), and to examine potential ethnic differences in drug exposure between Chinese and the global patient populations using both population and non-compartmental PK methods. Methods: An ongoing clinical phase 2 bridging study in China had enrolled 29 advanced GIST patients who underwent intensive or sparse PK sampling at a ripretinib dose of 150 mg QD. The plasma samples were collected and then analyzed with LC-MS/MS to quantitatively determine the concentration of ripretinib and its active metabolite. Non-compartmental analysis (NCA) was performed using Phoenix WinNonlin® software and population PK analysis was conducted with nonlinear mixed-effect modeling (NONMEM) and R software. In total, there were 15 Chinese GIST patients included in the NCA analysis and 379 patients (350 from global studies and 29 from China bridging study) were involved in the population PK analysis. Evaluation of potential exposure differences between the Chinese population and the global population were based on steady state NCA data and population PK modeling results. Results: Based on the NCA results, the PK exposure of ripretinib and its active metabolite in the Chinese population were similar to that in the global population: 1) The steady state AUC of parent drug (geometric mean of AUC0-12 was 7280 hr*ng/mL, CV 53.8%) in Chinese patients showed differences of 28.2% compared with the global population. 2) The steady state AUC of active metabolite (geometric mean of AUC0-12 was 8490 hr*ng/mL, CV 80.7%) in Chinese patients showed differences of 19.1% compared with the global population. 3) For Cmax of parent drug in Chinese patients, the multiple dosing (geometric mean of Cmax was 787 ng/mL, CV 50.2%) showed differences of 3.4% compared with the global population. 4) For Cmax of active metabolite in Chinese patients, the multiple dosing (geometric mean of Cmax was 860 ng/mL, CV 72.2%) showed differences of 7.0% compared with the global population. In addition, the population PK results showed no ethnical effect on steady-state exposure of parent and its active metabolite between Asians and non-Asians (p > 0.05) and between Chinese and non-Chinese patients (p > 0.05). Conclusion: Based on population PK modeling data and the NCA results of ripretinib and its active metabolite, no significant PK differences were observed between the Chinese patient population and the global patient population.

Citation Format: Jian Li, Jun Zhang, Xingye Wu, Chao Wu, Juan Dong, Liang Huang, Lin Shen. Population and non-compartmental pharmacokinetic analysis of ripretinib and its active metabolite in Chinese patients with gastrointestinal stromal tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB126.