Regorafenib treatment improves survival of patients with metastatic colorectal cancer, but it is also characterized by detrimental side effects that may require modified dosing or interval schedules. Regorafenib is metabolized by cytochrome P450 3A4 in the liver to its active metabolites, M‐2 and M‐5. We examined area under the unbound plasma concentration‐time curve (AUCu) to these compounds to establish pharmacokinetic bases for individualized dosing strategies. The plasma protein binding of M‐2 and M‐5 was approximately 10‐fold lower than that of regorafenib, whereas AUCu values for active metabolites on both days 1 and 15 were significantly higher than that of regorafenib. Patients with higher AUCu values of M‐2 or M‐5 on day 1 showed significantly shorter progression‐free survival than others, likely due, at least in part, to treatment discontinuation as a result of adverse events, especially occurred during first cycle.

中文翻译：

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瑞格非尼未结合的活性代谢物的更高的全身暴露与大肠癌患者的无进展生存期短有关。

Regorafenib治疗可改善转移性结直肠癌患者的生存，但其特征还在于有害副作用，可能需要调整剂量或间隔时间。Regorafenib在肝脏中被细胞色素P450 3A4代谢成其活性代谢物M-2和M-5。我们检查了这些化合物的未结合血浆浓度-时间曲线（AUCu）下的面积，以建立针对个体给药策略的药代动力学基础。M-2和M-5的血浆蛋白结合率比regorafenib低约10倍，而活性代谢产物在第1天和第15天的AUCu值均显着高于regorafenib。第1天的AUCu值为M-2或M-5较高的患者，其无进展生存期明显短于其他患者，这可能至少部分原因是：