Development and analytical validation of a new LC-MS/MS method for the simultaneous quantification of imatinib and cabozantinib: application for Therapeutic Drug Monitoring in cancer patients.

Imatinib and cabozantinib are tyrosine kinase inhibitors used in the treatment of gastrointestinal stromal tumors (GISTs) and metastatic renal cell carcinoma (mRCC), respectively. Like many oral anticancer drugs (OADs), they are characterized by a narrow therapeutic window and show significant interindividual variability in plasma concentrations, which may result in suboptimal outcomes such as therapeutic failure or dose-related toxicity. For these reasons, both agents are good candidates for therapeutic drug monitoring (TDM), a clinical practice aimed at ensuring that drug levels remain within the therapeutic range to optimize efficacy and safety. The objective of this thesis was the development and analytical validation of a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of imatinib and cabozantinib in human plasma, in accordance with the FDA ICH M10 guidelines on bioanalytical method validation. The method was optimized to provide high sensitivity, selectivity, accuracy, precision, and reproducibility, with evaluation of parameters such as linearity, matrix effect, recovery, and stability. In addition to the plasma method, a second analytical approach based on dried blood spot (DBS) sampling is currently under development. Preliminary experiments are ongoing to assess its feasibility, and the translational comparability of results obtained from plasma and DBS will also be evaluated, with the aim of establishing a less invasive alternative to venous blood collection. The validated plasma method, together with the preliminary DBS data, represents a valuable step toward the reliable quantification of imatinib and cabozantinib in clinical samples, supporting the implementation of TDM and contributing to more personalized pharmacotherapy in oncology.