A simple and rapid liquid chromatography-mass spectrometry method to assay cabozantinib in plasma: Application to therapeutic drug monitoring in patients with renal cell carcinoma

Abstract

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 min. 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.