An LC-MS/MS method for the quantitation of cabozantinib in rat plasma: application to a pharmacokinetic study

A simple, rapid and sensitive high-performance liquid chromatography tandem mass-spectrometric method (LC-MS/MS) for the novel multiple tyrosine kinase inhibitor (TKI) cabozantinib was developed and validated using erlotinib as internal standard (IS). Plasma samples were pre-treated by liquid-liquid extraction with ethyl acetate. Separation was achieved on a reversed phase C18 column (50×2mm, 5μm) at ambient temperature using isocratic elution with acetonitrile-water (45:55, v/v) containing 5mM ammonium formate buffer (finally adjusted to apparent pH*=5.0 with formic acid) at a flow rate of 0.4mL/min. The analytes were monitored by a triple quadrupole tandem mass spectrometer with electrospray ionization source in the positive ion mode. Calibration curve was linear (r>0.99) in a concentration range of 0.5-1000ng/mL with the lower limit of quantification (LLOQ) of 0.5ng/mL. Intra- and inter-day accuracy and precision were validated by relative error values (RE) and relative standard deviation values (RSD), respectively, which were both lower than the limit of 15%. This method was successfully applied to a pharmacokinetic study of cabozantinib in rats.