Ogawa-Morita Tomoko, Sano Yoshiyuki, Okano Tomoka, Fujii Hirofumi, Tahara Makoto, Yamaguchi Masakazu, Minami Hironobu
Division of Pharmacy, National Cancer Center Hospital East, Chiba, Japan.
Division of Functional Imaging, National Cancer Center, Chiba, Japan.
Int J Anal Chem. 2017;2017:2341876. doi: 10.1155/2017/2341876. Epub 2017 Jun 7.
Toward conducting clinical pharmacokinetic studies of an antineoplastic agent, lenvatinib, we developed a liquid chromatography-tandem mass spectrometric assay for its quantitative analysis in human plasma. Analyte (lenvatinib) and internal standard (IS, propranolol) in the plasma were extracted by using acetonitrile and chromatographically separated by using a XTerra MS C18 column with 0.2 mL/min flow and mobile phase starting with 0.1% formic acid in water, followed by increasing percentage of acetonitrile. Detection was performed by using combined reversed-phase liquid chromatography-tandem mass spectrometry (LC/MS-MS) with positive ion electrospray ionization. MS-MS ion transitions used were 427.602>371.000 for lenvatinib and 260.064>116.005 for IS. This study was validated for accuracy, precision, linearity, range, selectivity, lower limit of quantification, recovery, and matrix effect according to the Guideline on Bioanalytical Method Validation in Pharmaceutical Development in Japan. Calibration curve was plotted by using lenvatinib concentrations ranging within 9.6-200 ng/mL, and correlation coefficients () were in excess of 0.997. Intra- and interday accuracy ranged within 95.8-108.3% with mean recoveries of 66.8% for lenvatinib, and precision was <6.7% at all quality control concentration levels. Matrix effect analysis showed extraction efficiency of 15.7% for lenvatinib. Collectively, these findings demonstrate the feasibility of this method to evaluate kinetic disposition of lenvatinib.
为了开展抗肿瘤药物乐伐替尼的临床药代动力学研究，我们开发了一种液相色谱 - 串联质谱分析法，用于定量分析人血浆中的乐伐替尼。血浆中的分析物（乐伐替尼）和内标（IS，普萘洛尔）用乙腈萃取，并使用XTerra MS C18柱进行色谱分离，流速为0.2 mL/min，流动相起始为0.1%甲酸水溶液，随后乙腈比例增加。采用正离子电喷雾电离的反相液相色谱 - 串联质谱联用（LC/MS-MS）进行检测。乐伐替尼的MS-MS离子跃迁为427.602>371.000，内标的离子跃迁为260.064>116.005。本研究根据日本药物研发生物分析方法验证指南，在准确性、精密度、线性、范围、选择性、定量下限、回收率和基质效应方面进行了验证。使用浓度范围在9.6 - 200 ng/mL的乐伐替尼绘制校准曲线，相关系数（）超过0.997。日内和日间准确性范围在95.8 - 108.3%之间，乐伐替尼的平均回收率为66.8%，在所有质量控制浓度水平下精密度均<6.7%。基质效应分析显示乐伐替尼的萃取效率为15.7%。总体而言，这些结果证明了该方法评估乐伐替尼动力学处置的可行性。
