Pralsetinib is a kinase inhibitor indicated for the treatment of metastatic rearranged during transfection (RET) fusion-positive non-small cell lung cancer. Pralsetinib is primarily eliminated by the liver and hence hepatic impairment (HI) is likely alter its pharmacokinetics (PK). Mild HI has been shown to have minimal impact on the PK of pralsetinib. This hepatic impairment study aimed to determine the pralsetinib PK, safety and tolerability in subjects with moderate and severe HI, as defined by the Child–Pugh and National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) classification systems, in comparison to subjects with normal hepatic function. Based on the Child–Pugh classification, subjects with moderate and severe HI had similar systemic exposure (area under the plasma concentration time curve from time 0 to infinity [AUC0–∞]) to pralsetinib, with AUC0–∞ geometric mean ratios (GMR) of 1.12 and 0.858, respectively, compared to subjects with normal hepatic function. Results based on the NCI-ODWG classification criteria were comparable; the AUC0–∞ GMR were 1.22 and 0.858, respectively, for subjects with moderate and severe HI per NCI-ODWG versus those with normal hepatic function. These results suggested that moderate and severe hepatic impairment did not have a meaningful impact on the exposure to pralsetinib, thus not warranting a dose adjustment in this population.

中文翻译：

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探索肝损伤对 Pralsetinib 药代动力学的影响


Pralsetinib 是一种激酶抑制剂，适用于治疗转染期间转移性重排 (RET) 融合阳性非小细胞肺癌。 Pralsetinib 主要通过肝脏消除，因此肝损伤 (HI) 可能会改变其药代动力学 (PK)。轻度 HI 已被证明对 pralsetinib 的 PK 影响极小。这项肝损伤研究旨在确定普拉替尼在中度和重度 HI 受试者中的 PK、安全性和耐受性（根据 Child-Pugh 和国家癌症研究所器官功能障碍工作组 (NCI-ODWG) 分类系统的定义），并与患有中度和重度 HI 的受试者进行比较。肝功能正常。根据 Child-Pugh 分类，中度和重度 HI 受试者对普拉替尼的全身暴露量（血浆浓度时间曲线下从时间 0 到无穷大的面积 [AUC0-∞]）相似，AUC0-∞ 几何平均比 (GMR)与肝功能正常的受试者相比，分别为 1.12 和 0.858。基于 NCI-ODWG 分类标准的结果具有可比性；根据 NCI-ODWG 的中度和重度 HI 受试者与肝功能正常的受试者相比，AUC0-∞ GMR 分别为 1.22 和 0.858。这些结果表明，中度和重度肝损伤对普拉替尼的暴露量没有有意义的影响，因此不需要在该人群中调整剂量。