Yang Guihong, Wang Yimei, Zhao Huimin, Jiang Ziyi, Zheng Shansong, Ge Mingjing, Si Meimei, Kang Xiaoyan
Qilu Pharmaceutical Co., Ltd, Jinan, Shandong, China.
Clin Transl Sci. 2025 Jan;18(1):e70099. doi: 10.1111/cts.70099.
Iruplinalkib (WX-0593), a selective oral ALK/ROS1 tyrosine kinase inhibitor, was approved in China as first-line therapy for ALK-positive non-small-cell lung cancer (NSCLC) and for the treatment of locally advanced or metastatic ALK-positive NSCLC that has progressed following crizotinib therapy. Pharmacokinetics (PK) data of iruplinalkib have been collected in healthy subjects and patient populations in several studies. We developed a population PK (PopPK) model for describing iruplinalkib plasma concentrations and for evaluating whether dose adjustments are necessary based on demographic factors or disease characteristics. Plasma concentration-time data were collected from 392 participants (16 healthy volunteers and 372 patients with solid tumors) who received single or multiple doses of iruplinalkib in four trials. Data were analyzed using non-linear mixed-effects modeling. Iruplinalkib plasma concentrations were best described by a two-compartment model with first-order absorption and first-order elimination. Baseline body weight, time-varying albumin, time-varying creatinine clearance, and time-varying lactate dehydrogenase were significant covariates of apparent clearance from the central compartment (CL/F) while baseline body weight was a significant covariate of apparent volume of the central compartment (V1/F). Given the small or modest effect of all statistically significant covariates on iruplinalkib exposure at steady-state, no covariate was expected to have clinically meaningful effects on iruplinalkib exposure. Furthermore, iruplinalkib absorption was delayed 0.472 h after meal, and K was 58.8% of that under fasting. However, there was no difference in exposure of iruplinalkib between the fasted and fed states. In conclusion, the PopPK model adequately describes iruplinalkib PK properties in Chinese healthy subjects and patients with solid tumors. No covariate had a clinically meaningful impact on iruplinalkib exposure. These results indicate that dose adjustment of iruplinalkib is not necessary, based on the aforementioned covariates, for ALK-positive NSCLC patients.
艾乐替尼（WX-0593）是一种选择性口服ALK/ROS1酪氨酸激酶抑制剂，在中国被批准作为ALK阳性非小细胞肺癌（NSCLC）的一线治疗药物，用于治疗克唑替尼治疗后进展的局部晚期或转移性ALK阳性NSCLC。在多项研究中，已在健康受试者和患者群体中收集了艾乐替尼的药代动力学（PK）数据。我们开发了一个群体PK（PopPK）模型，用于描述艾乐替尼的血浆浓度，并评估是否需要根据人口统计学因素或疾病特征进行剂量调整。在四项试验中，从392名接受单剂量或多剂量艾乐替尼的参与者（16名健康志愿者和372名实体瘤患者）中收集了血浆浓度-时间数据。使用非线性混合效应模型对数据进行分析。艾乐替尼的血浆浓度最好用具有一级吸收和一级消除的二室模型来描述。基线体重、随时间变化的白蛋白、随时间变化的肌酐清除率和随时间变化的乳酸脱氢酶是中央室表观清除率（CL/F）的显著协变量，而基线体重是中央室表观容积（V1/F）的显著协变量。鉴于所有具有统计学意义的协变量对稳态下艾乐替尼暴露的影响较小或适中，预计没有协变量会对艾乐替尼暴露产生临床意义上的影响。此外，进食后艾乐替尼的吸收延迟0.472小时，K值为禁食时的58.8%。然而，禁食和进食状态下艾乐替尼的暴露没有差异。总之，PopPK模型充分描述了艾乐替尼在中国健康受试者和实体瘤患者中的PK特性。没有协变量对艾乐替尼暴露有临床意义上的影响。这些结果表明，对于ALK阳性NSCLC患者，基于上述协变量，无需调整艾乐替尼的剂量。
