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Apatinib is a new oral micromolecular tyrosine kinase inhibitor, which is mainly used as a third-line treatment for chemotherapy-refractory advanced metastatic gastric cancer patients. However, apatinib has shown dose titration and severe adverse reactions in clinical practice. Quantification of the plasma concentrations of apatinib may be an effective method to balance the clinical efficacy and adverse reactions. The purpose of this study was to develop and validate a two-dimensional liquid chromatography method for the measurement of apatinib in plasma.The analysis of apatinib was performed using a two-dimensional high-performance liquid chromatography system (HPLC). We precipitated the proteins with acetonitrile. The mobile phases consisted of first-dimensional mobile phase (acetonitrile:methanol:25 mmol·L-1 ammonium phosphate = 25:25:50, V/V/V, pH adjusted to 7.2 using phosphoric acid) and second-dimensional mobile phase (acetonitrile:10 mmol·L-1 ammonium phosphate = 28:72, V/V, pH adjusted to 3.7 by phosphoric acid). The ultraviolet detection wavelength was set at 340 nm. The temperature of the detector cell was 40 °C and the injection volume was 500 μL.The range of calibration curve was 15.27-1491.48 ng/mL. The accuracy and imprecision were within ± 2.23% and less than 10.22%, respectively (intra- and inter-day). The range of recovery was 97.45%-108.92%. The intra- and inter-day relative standard deviation (reproducibility) of HPLC retention times were less than 0.18% and 0.46%, respectively. In the clinical assessment, the dose range apatinib mesylate for patients with gastric cancer was 250-500 mg every day (2 days-60 days), resulting in trough plasma concentrations between 272.7 and 727.8 ng/mL.A simple, convenient, accurate and robust two-dimensional liquid chromatography method was developed and verified, which successfully determined the plasma concentrations of apatinib in gastric cancer patients.