背景:阿列替尼,克唑替尼,和ceritinib,是间变性淋巴瘤激酶-酪氨酸激酶抑制剂(ALK-TKIs),表现出高蛋白结合,它们的代谢与细胞色素P450(CYP)同工酶2C9或3A4有关。华法林的血浆蛋白结合率,用于预防和治疗静脉血栓栓塞,也很高。华法林是S-华法林和R-华法林的外消旋体,它们分别由CYP2C9和CYP3A4代谢。目前缺乏关于上述ALK-TKIs和华法林之间的药物相互作用以及同时使用bucolome的报道。
方法:我们报告了一例患者接受华法林和bucolome,其国际标准化比率(INR)在阿来替尼序贯治疗后增加,克唑替尼,和ceritinib.该患者是一名61岁的男性,有主动脉瓣反流病史,主动脉瓣置换术后接受华法林治疗的患者。Bucolome,可以增强华法林的效果,同时使用。患者被诊断为原发性肺腺癌,在二线化疗期间检测到ALK重排。化疗后疾病进展,阿莱替尼序贯治疗,克唑替尼,和ceritinib开始。治疗前INR值在治疗范围内(目标INR为2-3),但每次在开始阿来替尼后增加至治疗前水平,克唑替尼,或ceritinib治疗。调整华法林剂量或停药是维持治疗INR范围所必需的。没有发生严重的出血事件或饮食摄入量的实质性变化。阿来替尼取代血浆蛋白结合或竞争性抑制代谢,克唑替尼,和ceritinib可以增加未结合形式的华法林的血浆浓度,导致高INR值。此外,阿列替尼,克唑替尼,和ceritinib可能会导致从血浆蛋白中置换出bucolome,其次是华法林的移位或抑制华法林代谢引起的未结合形式的口腔体。
结论:阿来替尼治疗期间需要密切监测INR和调整华法林剂量,克唑替尼,或ceritinib在接受华法林同时使用bucolome的患者中。
BACKGROUND: Alectinib, crizotinib, and ceritinib, are anaplastic lymphoma kinase-tyrosine kinase inhibitors (ALK-TKIs) that exhibit high protein binding, and their metabolism is associated with the cytochrome P450 (CYP) isoenzymes 2C9 or 3A4. The plasma protein binding rate of warfarin, which is used to prevent and treat venous thromboembolism, is also high. Warfarin is a racemate of S-warfarin and R-warfarin, which are metabolized by CYP2C9 and CYP3A4, respectively. Reports on the drug interactions between each of the above-mentioned ALK-TKIs and warfarin with concurrent use of bucolome are currently lacking.
METHODS: We report a case of a patient receiving warfarin and bucolome, whose international normalized ratio (INR) increased after sequential treatment with alectinib, crizotinib, and ceritinib. The patient was a 61-year-old man with a history of aortic valve regurgitation, who was receiving warfarin treatment following aortic valve replacement. Bucolome, which can enhance the effect of warfarin, was also used simultaneously. The patient was diagnosed with primary lung adenocarcinoma, and ALK rearrangement was detected during second-line chemotherapy. After progression of the disease with chemotherapy, sequential treatment with alectinib, crizotinib, and ceritinib was initiated. Pretreatment INR values were in the therapeutic range (target INR of 2-3) but increased to supratherapeutic levels each time after initiation of alectinib, crizotinib, or ceritinib treatment. Adjustment of warfarin dose or discontinuation of bucolome were necessary to maintain the therapeutic INR range. There were no serious bleeding events or substantial changes in dietary intake. Displacement of plasma protein binding or competitive inhibition of metabolism by alectinib, crizotinib, and ceritinib could increase the plasma concentration of the unbound form of warfarin, resulting in high INR values. In addition, alectinib, crizotinib, and ceritinib might cause displacement of bucolome from plasma proteins, followed by displacement of warfarin or inhibition of warfarin metabolism caused by the unbound form of bucolome.
CONCLUSIONS: Close monitoring of INR and adjustment of warfarin dosage are needed during treatment with alectinib, crizotinib, or ceritinib in patients who receive warfarin with concurrent use of bucolome.