Cabozantinib is a novel multi-target tyrosine kinase inhibitor recently approved in metastatic renal cell carcinoma (mRCC) leading to frequent severe toxicities requiring empirical dose reduction. Therapeutic drug monitoring (TDM) could help to predict the risk for severe toxicities by quickly detecting overexposed patients followed by prospective adaptive dosing strategy. To achieve this goal, a simple and rapid assay to monitor cabozantinib plasma concentration was developed and validated. After a single precipitation step with 87% recovery, cabozantinib was assayed by liquid chromatography tandem mass spectrometry (electrospray ionization interface) over a 25- 5000 ng/ml range covering usual plasma levels in clinical setting. For cabozantinib and cabozantinib 2H4 used as internal standard, quantification was performed using the m/z 502 → m/z 323 and m/z 506 → m/z 323 transitions, respectively.Analytical runtime was 5 minutes. Both inter-days and intra-day accuracy and precision were <15%. When tested in routine clinical practice in a subset of mRCC patients treated with standard 60 mg quaque die (QD) dosing, the method proved to be fully adapted and neither analytical interferences nor matrix effect was observed. Results showed that cabozantinib trough levels were highly variable among patients (i.e., 973 ±501 ng/ml, CV = 52%), calling for implementing TDM in patients with mRCC to monitor exposure levels and evaluate concentration-response relationship.

Cabozantinib是一种新型的多靶酪氨酸激酶抑制剂，最近在转移性肾细胞癌（mRCC）中获得批准，导致频繁的严重毒性反应，需要减少经验剂量。通过快速检测过度暴露的患者，然后采用前瞻性的适应性给药策略，治疗药物监测（TDM）可以帮助预测严重毒性的风险。为了实现这一目标，开发并验证了一种简单快速的监测卡博替尼血浆浓度的测定方法。在单一沉淀步骤中，回收率达到87％之后，卡波替尼通过液相色谱串联质谱法（电喷雾电离界面）在25-5000 ng / ml范围内进行测定，涵盖临床环境中的常规血浆水平。对于卡博替尼和卡博替尼2H4用作内标物，使用m / z 502→ m / z 323和m / z 506→ m / z 323转换。分析运行时间为5分钟。日间和日内准确性和精确度均低于15％。当在接受标准60 mg quaque die（QD）剂量治疗的一部分mRCC患者的常规临床实践中进行测试时，该方法被证明是完全适用的，并且未观察到分析干扰或基质效应。结果显示卡波替尼谷水平在患者之间变化很大（即973±501 ng / ml，CV = 52％），这要求在mRCC患者中实施TDM监测暴露水平并评估浓度-反应关系。