HPLC-MS Quantification of Multiple Tyrosine Kinase Inhibitors in Patients with Solid Tumors: Method Validation and Clinical Application.

Objectives: A high-performance liquid chromatography (HPLC) with mass spectrometry (MS) detection method was developed to quantify several tyrosine kinase inhibitors (TKIs) and their relevant metabolites. This method is suitable for therapeutic drug monitoring (TDM) of alectinib, brigatinib, dabrafenib, lenvatinib, lorlatinib, osimertinib and trametinib in patients with solid tumors using volumetric absorptive microsampling (VAMS®). Methods: The HPLC-MS system contained four pumps, a Turboflow HTLC CycloneTM 1.0 × 50 mm solid phase extraction column for analyte enrichment, and a Kinetex 2.6 µm C18 100Å, 100 × 3.0 mm column for analyte separation. An acetonitrile-water gradient was used for the separation, and the ions generated by ESI (+)-ionization were detected in single-ion mode. This method was validated according to recent European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines. Results: The accuracy and precision shown during method validation were within the acceptable limits for all analytes in plasma and whole blood. All analytes showed acceptable stability in both matrices for at least 28 days when stored at -21 °C. So far, 100 venous plasma and 94 capillary blood samples have been collected and analyzed. Conclusions: We developed a reliable method to quantify several TKIs from plasma and capillary blood, which is intended for TDM purposes in clinical practice.