Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers
Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers
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DOI：
10.1007/s00280-021-04237-x
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发表时间：
2021-02-26
影响因子：
3
通讯作者：
Yamaguchi, Kensei
中科院分区：
文献类型：
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作者：
Kobayashi, Kazuo;Sugiyama, Erika;Yamaguchi, Kensei
目的多重酪氨酸激酶抑制剂瑞格拉非尼的药代动力学和药效学之间的关系尚不清楚。这项研究评估了转移性结直肠癌患者瑞格拉非尼及其N-氧化物(M2)和N-氧化物/脱甲基(M5)代谢产物的低谷血浆浓度(C谷)，并评估了这些水平、不良事件和药代动力学相关基因多态性之间的关系。方法采用单中心前瞻性观察性研究，在初始治疗7天后评价瑞格拉非尼及其代谢物的C-谷值。然后检查这些值与不良事件之间的相关性。此外，还检测了ABCG2、SLCO1B1和UGT1A9的遗传多态，并对其与瑞格非尼、M2和M5水平的相关性进行了评估。结果我们分析了43例服用瑞格非尼40~120 mg/d的患者，其中35例从120 mg/d开始。在胆红素升高方面，>；=2级组的C-谷值显著高于0级组和1级组(p=0.010)。M5C-谷值与高血压或皮疹的严重程度显著相关(p<；0.05)。在多变量分析中，M5C-谷值和年龄是严重皮疹的显著预测因素。ABCG2421A/A和ABCG2421C/A或C/C基因多态患者的M5浓度-剂量比差异有统计学意义(P=0.035)。结论Regorafenib的C谷与胆红素升高有关，首次明确M5的C谷与高血压和严重皮疹显著相关。
Purpose The association between the pharmacokinetics and pharmacodynamics of regorafenib, a multiple tyrosine kinase inhibitor, remains unclear. This study assessed the trough plasma concentrations (C-trough) of regorafenib and its N-oxide (M2) and N-oxide/desmethyl (M5) metabolites, and evaluated the associations among these levels, adverse events, and pharmacokinetic-related genetic polymorphisms in patients with metastatic colorectal cancer. Methods The C-trough levels of regorafenib and its metabolites were assessed in a single-center, prospective, observational study, 7 days after the initial treatment. The correlation between those values and adverse events was then examined. In addition, the genetic polymorphisms of ABCG2, SLCO1B1, and UGT1A9 were determined and evaluated for associations with the levels of regorafenib, M2, and M5. Results We analyzed 43 patients who received regorafenib 40-120 mg/day; among them, 35 patients started at 120 mg/day. With regard to bilirubin increase, the C-trough values of regorafenib were significantly higher in the group with grade >= 2 than in groups with grades 0 and 1 (p = 0.010). The M5 C-trough levels were significantly associated with the severity of hypertension or rash (p < 0.05). In a multivariate analysis, the M5 C-trough values and age were significant predictors of severe rash. Lastly, significant differences were noted in the M5 concentration-to-dose ratio values between the patients with ABCG2 421A/A and ABCG2 421C/A or C/C polymorphisms (p = 0.035). Conclusion This study showed that the C-trough of regorafenib was associated with bilirubin increase, and also clarified for the first time that the C-trough of M5 was significantly correlated with hypertension and severe rash.