Simultaneous determination of nine tyrosine kinase inhibitors by 96-well solid-phase extraction and ultra performance LC/MS-MS.

ABSTRACT

BACKGROUND: Tyrosine Kinase Inhibitors (TKIs) are a class of targeted drugs for the treatment of malignant pathologies. The metabolic profile of these drugs can result in great interindividual variability, thus therapeutic drug monitoring (TDM) is of importance. Here, a rapid and specific method for quantification of nine TKIs in plasma samples is described. METHODS: Chromatography was performed on a Waters Acquity-UPLC® system with BEH C18-50*2.1 mm column, under a gradient of ammonium formate-acetonitrile. An Acquity-TQD® with electrospray ionization was used for detection. Samples were prepared by solid phase extraction (Oasis® MCX µElution) and eluate was injected in the system. RESULTS: Calibration curves ranged from 10 to 5000 ng/mL for imatinib, its metabolite, nilotinib, lapatinib, erlotinib and sorafenib and from 0.1 to 200 ng/mL for dasatinib, axitinib, gefitinib and sunitinib. Peaks of each compound (retention time from 0.76 to 2.51 min) were adequately separated. The mean relative extraction recovery was in the range of 90.3-106.5% thanks to the use of stable isotopes as internal standard. There was no significant ion suppression observed at the respective TKI retention times. CONCLUSION: This rapid, sensitive and specific UPLC/MS-MS method is able to perform simultaneous quantification of nine TKIs in human plasma and usable for routine TDM.