Lenvatinib has been demonstrated effective in advanced hepatocellular carcinoma (HCC), but the pharmacokinetic-pharmacodynamics behavior of lenvatinib and its metabolites remains unclear. To investigate the pharmacokinetic-pharmacodynamics behavior of lenvatinib and its active metabolites in advanced HCC patients, it is important to develop a simple and rapid method to analyze the exposures of lenvatinib and its metabolites in human samples. Here, we established and validated a simple and rapid method for determining lenvatinib and its three major metabolites, descyclopropyl lenvatinib (M1), O-demethyl lenvatinib hydrochloride (M2), and lenvatinib N-Oxide (M3) by liquid chromatography-tandem mass spectrometry method. Lenvatinib and its main metabolites were separated on an X-Terra RP18 column (50 × 2.1 mm, 3.5 µm) at 35°C within 3 min, and the analytes were isocratically eluted with the mobile phase of methanol-water (10:90, v/v) containing 0.1% of formic acid at a flow rate of 0.15 mL/min. The calibration range was 1-1000 ng/mL for lenvatinib, while 0.1-100 ng/mL for M1-M3 under positive electrospray ionization mode. The inter- and intra-batch precisions and accuracy were acceptable for lenvatinib and its metabolites. This method was successfully applied to measure lenvatinib and its metabolites in plasma samples from HCC patients, which provides a robust tool for pharmacokinetic-pharmacodynamics studies of lenvatinib.
Keywords: HCC patients; lenvatinib; liquid chromatography‐tandem mass spectrometry; metabolites; method validation.
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