Quantitative determination of plasma cabozantinib concentration using HPLC–UV and its application to patients with renal cell carcinoma

Abstract

Cabozantinib is an oral small-molecule tyrosine kinase inhibitor that has become a standard of care for advanced renal cell carcinoma (RCC). However, cabozantinib is associated with a high rate of adverse events. Therefore, individualised cabozantinib administration and monitoring could help maximise its therapeutic efficacy and avoid serious adverse events. This study developed and validated a method to determine cabozantinib concentration in plasma using HPLC-UV. Sorafenib, an internal standard, was added to the plasma sample containing cabozantinib. A calibration curve for cabozantinib showed good linearity (R 2 = 1.00), between 25 and 4,000 ng/ml. The recovery rate was above 92.1%, and the intra-and inter-day coefficients of variation were smaller than 5.2 and 6.8%, respectively. Then, we applied the method for monitoring cabozantinib blood levels in three patients with advanced RCC who were taking cabozantinib at a dose of 20, 40 or 60 mg/day. Grade 3 adverse events were more likely to occur in patients with high dosing and blood level of cabozantinib. Owing to its simplicity, the developed method can be used in general hospitals, and is expected to help maximise drug efficacy and minimise serious adverse events in many patients with RCC undergoing cabozantinib treatment.

Plasma Cabozantinib Level Measurement in Patients with Renal Cell and Hepatocellular Carcinomas Using a Simple HPLC–UV Method Suitable for Clinical Application

“…Maruyama et al [11] developed the first quantitative method for cabozantinib detection using HPLC-UV, reporting a quantitative concentration range of 0.02-4 µg/mL, which is lower than our quantitative concentration range. However, a therapeutic window between 0.5 and 1.5 µg/mL has been proposed for cabozantinib trough levels to ensure an acceptable balance between effectiveness and toxicity [14].…”

“…The intraday and interday CV were 3.26% and 2.52%, respectively, with this method, compared to 5.2% and 6.8%, respectively, with the previous method. In addition, the intraday and interday accuracies were −4.35% to 0.79% and −1.05% to 0.98% [11], respectively, with this method, compared with 0.6% to 10.1% and 0.3% to 9.7%, respectively, with the previous method. Third, the initial investment is low and the procedure is simple because few instruments are used for sample preparation.…”

“…A method for measuring cabozantinib concentrations in human plasma was developed using LC-MS/MS, with linearity over a concentration range of 0.025-5 µg/mL [10]. This method is superior to the previous method [11] in four respects. First, the time from sample preparation to measurement, including measurement time, is approximately 30 min less per sample.…”

“…High-performance liquid chromatography-ultraviolet (HPLC-UV) is more affordable than LC-MS/MS and is more suitable for routine TDM. Recently, an HPLC-UV method was reported to measure plasma cabozantinib concentrations [11]. In this study, we developed a simple and sensitive HPLC-UV method to quantify the concentration of cabozantinib in human plasma for clinical application with a more convenient pretreatment than the previous HPLC-UV method [11].…”

“…Recently, an HPLC-UV method was reported to measure plasma cabozantinib concentrations [11]. In this study, we developed a simple and sensitive HPLC-UV method to quantify the concentration of cabozantinib in human plasma for clinical application with a more convenient pretreatment than the previous HPLC-UV method [11]. To enable this assay to be applied in personalized medicine in a large number of patients, the effect of frequently used concomitant medications was assessed in patients receiving cabozantinib using real-world data.…”