Quantification of sorafenib, lenvatinib, and apatinib in human plasma for therapeutic drug monitoring by UPLC-MS/MS.

ABSTRACT

Sorafenib, lenvatinib, and apatinib, as multi-targeted tyrosine kinase inhibitors with anti-proliferative and anti-angiogenic effects, are widely used for systemic therapy in advanced hepatocellular carcinoma patients. Nevertheless, insufficient efficacy or adverse effects often appear due to the significant inter-individual variability of plasma concentration for these drugs. In order to carry out therapeutic drug monitoring of these drugs and then ensure the effectiveness and safety of the medical treatment, the first method allowing to quantify sorafenib, lenvatinib, and apatinib simultaneously in human plasma was developed in this study. The analysis was performed by UPLC-MS/MS system and the chromatographic separation was achieved on a C18 column using a gradient elution of water-acetonitrile in 3.5 min. This method presented satisfactory results in terms of specificity, precision (coefficient of variation of intra-day and inter-day1.4-6.6 %), accuracy (92.6-105.4 %), matrix effects (96.9-107.2 %), extraction recovery (90.5-99.4 %), as well as stability in human plasma and even whole blood under certain conditions. This sensitive, rapid and simple method was successfully applied to the analysis of sorafenib, lenvatinib and apatinib for therapeutic drug monitoring in hepatocellular carcinoma patients, and it was expected to be applied to further study about clarifying the concentration- efficacy and concentration-toxic relationship of sorafenib, lenvatinib, and apatinib in hepatocellular carcinoma patients.