Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Miyagi, Japan.
Department of Urology, Tohoku University Hospital, Sendai, Miyagi, Japan.
J Pharm Pharm Sci. 2020;23:200-205. doi: 10.18433/jpps30868.
Pazopanib is an orally available multi-tyrosine kinase inhibitor and has been used to treat renal cell carcinoma (RCC). Here, we report the case of a patient with RCC with an increased prothrombin time- international normalized ratio (PT-INR) due to pazopanib therapy. In addition, we have reported the change in the blood levels of pazopanib. A 75-year-old man underwent a left nephrectomy for RCC. Four years later, his cancer recurred and pazopanib therapy was initiated. He was also taking warfarin for atrial fibrillation and his PT-INR was constant at approximately 2. His warfarin dose was reduced from 3.5 mg/day to 3.0 mg/day on day 10 because his PT-INR increased from 2.19 to 3.07 compared to that before starting pazopanib. On day 28, his PT-INR further increased to 4.34, and his aspartate aminotransferase, alanine transaminase, and alkaline phosphatase levels increased. The target concentration of pazopanib was 20.5 to 50.3 µg/mL, but his blood concentrations were 92.1 µg/mL on day 6 and 93.7 µg/mL on day 13. Therefore, both pazopanib and warfarin were discontinued. One week later, his laboratory tests recovered, and hence, warfarin treatment was resumed. However, pazopanib therapy was terminated due to concerns about liver dysfunction. His hepatic dysfunction and increased PT-INR were considered to be due to pazopanib treatment. Pazopanib has been reported to have no effect on the pharmacokinetics of warfarin in clinical patients. In this case, blood levels of pazopanib were abnormally high, possibly causing liver dysfunction and drug interactions, leading to his PT-INR prolongation. TDM monitoring, in addition to the recommended monitoring for pazopanib hepatotoxicity, may help identify patients at risk for drug interactions. For patients receiving concomitant pazopanib and warfarin, close monitoring of PT-INR is warranted.
帕唑帕尼是一种可口服的多靶点酪氨酸激酶抑制剂，已被用于治疗肾细胞癌（RCC）。在这里，我们报告了一例因帕唑帕尼治疗而导致凝血酶原时间国际标准化比值（PT-INR）升高的 RCC 患者。此外，我们还报告了帕唑帕尼血药浓度的变化。一名 75 岁男性因 RCC 接受了左肾切除术。四年后，他的癌症复发并开始接受帕唑帕尼治疗。他还因心房颤动服用华法林，他的 PT-INR 一直稳定在约 2。他的华法林剂量从每天 3.5 毫克减少到 3.0 毫克，因为他的 PT-INR 从开始使用帕唑帕尼前的 2.19 增加到 3.07。第 28 天，他的 PT-INR 进一步增加到 4.34，他的天冬氨酸氨基转移酶、丙氨酸转氨酶和碱性磷酸酶水平升高。帕唑帕尼的目标浓度为 20.5 至 50.3μg/ml，但他的血药浓度在第 6 天为 92.1μg/ml，第 13 天为 93.7μg/ml。因此，同时停用了帕唑帕尼和华法林。一周后，他的实验室检查结果恢复正常，因此恢复了华法林治疗。然而，由于担心肝功能障碍，帕唑帕尼治疗被终止。他的肝功能障碍和 PT-INR 升高被认为是由帕唑帕尼治疗引起的。在临床患者中，已报道帕唑帕尼对华法林的药代动力学没有影响。在这种情况下，帕唑帕尼的血药浓度异常升高，可能导致肝功能障碍和药物相互作用，导致他的 PT-INR 延长。TDM 监测，除了推荐的帕唑帕尼肝毒性监测外，可能有助于识别有药物相互作用风险的患者。对于接受帕唑帕尼和华法林联合治疗的患者，需要密切监测 PT-INR。
