Cancer Medicine Department, Gustave Roussy, Université Paris-Saclay, Villejuif, France.
Medical Oncology Department, Hôpital Européen Georges Pompidou, AP-HP, Paris, France.
Oncologist. 2021 May;26(5):389-396. doi: 10.1002/onco.13711. Epub 2021 Feb 25.
Cabozantinib is an oral tyrosine kinase inhibitor that is approved for the treatment of metastatic renal cell carcinoma (mRCC). Cabozantinib is a weak base that exhibits a pH-dependent solubility profile in vitro which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPIs). The purpose of this study was to investigate whether PPI use has an impact on the efficacy, safety, and residual concentration (Ctrough) of cabozantinib in patients with mRCC.
This is a retrospective review of a prospectively collected electronic database of patients with mRCC who received cabozantinib at Gustave Roussy between February 2014 and December 2018. The Kaplan-Meier method was used for survival analysis and the Cox proportional-hazard model for uni- and multivariate analysis. In parallel, we conducted a pharmacokinetic study of cabozantinib in a distinct cohort of 50 mRCC patients, in which cabozantinib Ctrough was assayed using a validated tandem mass spectrometry-liquid chromatography method.
We identified 99 patients treated with cabozantinib, including 43 patients being PPI users. With a median follow-up of 30.3 months, PPI users showed similar progression-free survival and overall survival outcomes compared with PPI nonusers. Similarly, the incidence of adverse events was not significantly different between the PPI users and nonusers, although PPI users required dose reductions more often. In the independent pharmacokinetic cohort, of whom 21 received PPI concomitantly, Ctrough was similar between the two groups.
In line with the pharmacologic data, the concomitant use of PPI does not significantly impact the efficacy or safety of cabozantinib in patients with mRCC.
Drug interactions, especially between targeted therapies and proton pump inhibitors (PPI), were shown to potentially impact the outcomes of cancer patients. Cabozantinib, a current therapeutic standard in metastatic renal cell carcinoma (mRCC), exhibits a pH-dependent solubility profile, which raises concerns about its bioavailability in patients treated with proton pump inhibitors (PPI). At the present time, there is no evidence regarding the effect of PPIs on cabozantinib's efficacy and safety in patients with mRCC. This study found that the concomitant use of PPI during cabozantinib treatment in mRCC patients does not appear to impact the residual concentration, efficacy, and safety of cabozantinib in a real-life context.
卡博替尼是一种口服酪氨酸激酶抑制剂，已被批准用于治疗转移性肾细胞癌（mRCC）。卡博替尼是一种弱碱，在体外表现出 pH 依赖性溶解度特征，这引起了人们对接受质子泵抑制剂（PPIs）治疗的患者其生物利用度的关注。本研究旨在探讨 PPI 的使用是否会影响 mRCC 患者卡博替尼的疗效、安全性和残留浓度（Ctrough）。
这是对 Gustave Roussy 于 2014 年 2 月至 2018 年 12 月期间接受卡博替尼治疗的 mRCC 患者前瞻性电子数据库进行的回顾性研究。采用 Kaplan-Meier 法进行生存分析，采用 Cox 比例风险模型进行单变量和多变量分析。同时，我们对 50 例 mRCC 患者进行了卡博替尼的药代动力学研究，其中使用了经过验证的串联质谱-液相色谱法来测定卡博替尼的 Ctrough。
我们确定了 99 例接受卡博替尼治疗的患者，其中 43 例为 PPI 使用者。中位随访 30.3 个月后，PPI 使用者与 PPI 非使用者的无进展生存期和总生存期结果相似。同样，PPI 使用者与非使用者的不良事件发生率也无显著差异，尽管 PPI 使用者更常需要减少剂量。在独立的药代动力学队列中，其中 21 例同时接受 PPI 治疗，两组之间的 Ctrough 相似。
与药代动力学数据一致，PPI 的同时使用不会显著影响 mRCC 患者卡博替尼的疗效或安全性。
药物相互作用，特别是靶向治疗与质子泵抑制剂（PPI）之间的相互作用，可能会影响癌症患者的治疗结果。卡博替尼是转移性肾细胞癌（mRCC）的当前治疗标准，其表现出 pH 依赖性溶解度特征，这引起了人们对接受质子泵抑制剂（PPI）治疗的患者其生物利用度的关注。目前，尚无关于 PPI 对 mRCC 患者卡博替尼疗效和安全性影响的证据。本研究发现，在 mRCC 患者中，卡博替尼治疗期间同时使用 PPI 似乎不会影响卡博替尼的残留浓度、疗效和安全性。
