Simultaneous analysis of anticancer agents bortezomib, imatinib, nilotinib, dasatinib, erlotinib, lapatinib, sorafenib, sunitinib and vandetanib in human plasma using LC/MS/MS

A new liquid chromatography–tandem mass spectrometry (LC–MS/MS) method, performed by electrospray ionization in positive mode using a triple quadrupole mass spectrometry, has been developed and validated for the simultaneous determination of bortezomib (BORT), dasatinib (DASA), imatinib (IMAT), nilotinib (NILO), erlotinib (ERLO), lapatinib (LAPA), sorafenib (SORA), sunitinib (SUNI) and vandetanib (VAND) in human plasma. Separation is achieved on an Hypersil Gold® PFP column using a gradient elution of 10 mM ammonium formate containing 0.1% formic acid (A) and acetonitrile containing 0.1% formic acid (B) at a flow rate of 0.3 mL/min. After addition of the internal standard and protein precipitation, the supernatant is diluted 2-fold in a mixture A and B (50/50, v/v). Two selected reaction monitoring transitions are used for each analyte: one is used for quantitation, the second one is used for confirmation. The standard curves are ranged from 2 ng/mL to 250 ng/mL for BORT, DASA and SUNI and from 50 ng/mL to 3500 ng/mL for the others and were fitted to a 1/x weighted linear regression model. The lowest limits of quantification were 2 ng/mL for BORT, DASA and SUNI and 50 ng/mL for the other TKIs. The method also showed satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-day RSD from 3.7% to 13.8%), accuracy (from 86.8% to 113.5%), recovery as well as stability of the analytes under various conditions. The method also may contribute to better understand the relationship between pharmacokinetics and pharmacodynamics of TKIs in hematological malignancies and solid tumors.

► The quantification of nine inhibitors of tyrosine kinase in a single run.
► The improvement of the specificity using LCMSMS and confirmation/quantification ions ratios.
► The ability to add in our method new ITKs that could have an interest in clinical practices.
► The large dynamic ranges of concentrations that allow to carry out some pharmacokinetics studies.