Liu Yinhui, Tan Yan, Hu Lin, Li Jinlong, Yang Jiansong, Diao Lei, Yang Jin
Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, China.
Shanghai Fosun Pharmaceutical Development Co., Ltd., Shanghai, China.
Front Pharmacol. 2024 Jul 16;15:1418549. doi: 10.3389/fphar.2024.1418549. eCollection 2024.
SAF-189s is a potent ALK/ROS1 inhibitor that is currently in clinical development for treating advanced ALK+/ROS1+ non-small cell lung cancer (NSCLC). Comprehensive population pharmacokinetics (PopPK) and exposure-response models were developed to evaluate the efficacy and safety of SAF-189s by integrating data from two clinical studies.
The PopPK model was developed using plasma concentration data collected from patients with ALK+/ROS1+ advanced NSCLC (n = 299) and healthy subjects (n = 24). The covariates (demographics, laboratory values, subject types, and concomitant medications) were evaluated to determine their potential influence on the between-patient variability in the pharmacokinetics of SAF-189s. Individual exposure values were then used to investigate the relationships with the efficacy endpoints (overall response rate (ORR), progression-free survival (PFS), and duration of response (DOR)) and key safety endpoints (adverse events of interest).
The final PopPK model of SAF-189s was described by a one-compartment model with delayed first-order absorption and time-dependent elimination by allowing the clearance to decrease stepwise over time. Age was included as a covariate for apparent clearance (CL/F), while prior anti-cancer therapy in ALK+ patients (ALKPOT) was included for apparent volume of distribution (V/F). There were no apparent exposure-response relationships for any of the efficacy endpoints at doses of 80-210 mg. The relationship between exposure and safety suggested that a higher steady-state exposure was associated with more frequent incidences of hyperglycemia and proteinuria; the 210-mg dose group was also less tolerated than the other low-dose groups.
PopPK and exposure-response models were developed for SAF-189s, and their results demonstrate that SAF-189s exposures are at the plateau of exposure-response for efficacy. The 210-mg dose group had a significantly higher safety risk, while the 160-mg dose group was well-tolerated. Thus, 160 mg of SAF-189s once daily was selected as the recommended phase III dose for the ALK+/ROS1+ or ROS1+ NSCLC patients.
SAF-189s是一种强效的间变性淋巴瘤激酶（ALK）/ROS1抑制剂，目前正处于治疗晚期ALK+/ROS1+非小细胞肺癌（NSCLC）的临床开发阶段。通过整合两项临床研究的数据，建立了综合群体药代动力学（PopPK）和暴露-反应模型，以评估SAF-189s的疗效和安全性。
使用从ALK+/ROS1+晚期NSCLC患者（n = 299）和健康受试者（n = 24）收集的血浆浓度数据建立PopPK模型。评估协变量（人口统计学、实验室值、受试者类型和伴随用药），以确定它们对SAF-189s药代动力学中患者间变异性的潜在影响。然后使用个体暴露值来研究与疗效终点（总缓解率（ORR）、无进展生存期（PFS）和缓解持续时间（DOR））以及关键安全终点（感兴趣的不良事件）之间的关系。
SAF-189s的最终PopPK模型由一个具有延迟一级吸收和时间依赖性消除的单室模型描述，通过允许清除率随时间逐步降低来实现。年龄作为表观清除率（CL/F）的协变量，而ALK+患者的既往抗癌治疗（ALKPOT）作为表观分布容积（V/F）的协变量。在80 - 210 mg剂量下，任何疗效终点均无明显的暴露-反应关系。暴露与安全性之间的关系表明，较高的稳态暴露与更高频率的高血糖和蛋白尿发生率相关；210 mg剂量组的耐受性也低于其他低剂量组。
为SAF-189s建立了PopPK和暴露-反应模型，其结果表明SAF-189s的暴露处于疗效暴露-反应的平台期。210 mg剂量组的安全风险显著更高，而160 mg剂量组耐受性良好。因此，选择每日一次160 mg的SAF-189s作为ALK+/ROS1+或ROS1+ NSCLC患者的推荐III期剂量。
