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Factors affecting high-grade hepatotoxicity of tyrosine kinase inhibitors in cancer patients: a multi-center observational study.
European Journal of Clinical Pharmacology ( IF 2.9 ) Pub Date : 2020-05-22 , DOI: 10.1007/s00228-020-02897-x
Ji Min Han 1, 2 , Hye Won Han 1, 3 , Jeong Yee 1 , Min Kyoung Kim 2, 4 , Jin Young Moon 1, 5 , Soyeon Cho 1, 3 , Dasom Jung 3, 4 , Yoon Sook Cho 2 , Inyoung Seo 5 , Jae Youn Kim 3 , Hye Sun Gwak 1
Affiliation  

PURPOSE Although several studies have examined tyrosine kinase inhibitor (TKI)-induced hepatotoxicity, the majority of patients in those studies displayed low-grade (grade I-II) hepatotoxicity. The purpose of this study was to investigate factors affecting high-grade (grade III-IV) hepatotoxicity of TKIs. METHODS This multi-center, retrospective study used individual patient data from five studies that examined factors affecting hepatotoxicity by TKIs (crizotinib, erlotinib, gefitinib, imatinib, and lapatinib). Odds ratio (OR) and adjusted OR (AOR) were estimated from univariate and multivariate analyses, respectively. RESULTS Data from 1279 patients treated with TKIs were analyzed. The rate of patients who experienced high-grade hepatotoxicity after TKI administration was 5.5%. In multivariable analysis, H2 blockers and CYP3A4 inducers increased high-grade hepatotoxicity 2.2- (95% CI 1.255-3.944) and 3.3-fold (95% CI 1.260-8.698), respectively. Patients with liver metastasis revealed a 3.4-fold (95% CI 1.561-7.466) higher risk of high-grade hepatotoxicity. Among underlying malignancies, pancreatic cancer and other cancers including acute lymphoblastic leukemia increased the risk of high-grade hepatotoxicity by 2.6- and 24.3-fold, respectively, whereas breast cancer decreased the risk (AOR 0.3, 95% CI 0.106-0.852), compared to non-small cell lung cancer. In patients who administrated TKIs which form reactive metabolites, use of CYP3A4 inducers and liver metastasis increased incidence of high-grade hepatotoxicity by 3.0- and 2.3-fold, respectively. In patients with EGFR mutation, exon 19 deletion and use of proton pump inhibitors were risk factors for high-grade hepatotoxicity in addition to liver metastasis and use of H2 blockers. CONCLUSION The use of H2 blockers, presence of liver metastasis, and CYP3A4 inducers were associated with high-grade hepatotoxicity of TKIs. In subgroup analyses, presence of exon 19 deletion, and/or proton pump inhibitors, was additional risk factors for high-grade hepatotoxicity in special patients and use of specific TKIs. Close liver function monitoring is recommended, especially in patients with liver metastasis or using H2 blockers or CYP3A4 inducers.

中文翻译:

影响癌症患者酪氨酸激酶抑制剂高度肝毒性的因素:一项多中心观察性研究。

目的尽管有几项研究检查了酪氨酸激酶抑制剂(TKI)诱导的肝毒性,但这些研究中的大多数患者表现出低度(I-II级)肝毒性。这项研究的目的是调查影响TKIs高等级(III-IV级)肝毒性的因素。方法这项多中心回顾性研究使用了来自五项研究的单个患者数据,这些研究检查了通过TKIs(克唑替尼,厄洛替尼,吉非替尼,伊马替尼和拉帕替尼)影响肝毒性的因素。赔率(OR)和调整后的OR(AOR)分别从单变量和多元分析中估算得出。结果分析了1279例接受TKI治疗的患者的数据。TKI给药后发生高度肝毒性的患者率为5.5%。在多变量分析中,H2受体阻滞剂和CYP3A4诱导剂分别增加高级别肝毒性2.2-(95%CI 1.255-3.944)和3.3倍(95%CI 1.260-8.698)。肝转移患者显示出高级别肝毒性的风险高3.4倍(95%CI 1.561-7.466)。在潜在的恶性肿瘤中,胰腺癌和其他癌症(包括急性淋巴细胞白血病)分别将高级别肝毒性的风险增加了2.6倍和24.3倍,而乳腺癌则降低了该风险(AOR 0.3、95%CI 0.106-0.852)非小细胞肺癌。在服用形成反应性代谢产物的TKIs的患者中,使用CYP3A4诱导剂和肝转移可使高级别肝毒性的发生率分别增加3.0-和2.3-倍。在EGFR突变患者中,除了肝脏转移和使用H2受体阻滞剂外,第19外显子的缺失和质子泵抑制剂的使用是高度肝毒性的危险因素。结论H2阻滞剂的使用,肝转移的存在和CYP3A4诱导剂与TKIs的高度肝毒性有关。在亚组分析中,外显子19缺失和/或质子泵抑制剂的存在是特殊患者高级别肝毒性和使用特定TKI的其他危险因素。建议密切监测肝功能,尤其是在有肝转移或使用H2受体阻滞剂或CYP3A4诱导剂的患者中。在亚组分析中,外显子19缺失和/或质子泵抑制剂的存在是特殊患者高级别肝毒性和使用特定TKI的其他危险因素。建议密切监测肝功能,尤其是在有肝转移或使用H2受体阻滞剂或CYP3A4诱导剂的患者中。在亚组分析中,外显子19缺失和/或质子泵抑制剂的存在是特殊患者高级别肝毒性和使用特定TKI的其他危险因素。建议密切监测肝功能,尤其是在有肝转移或使用H2受体阻滞剂或CYP3A4诱导剂的患者中。
更新日期:2020-05-22
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