A Broad Range High-Throughput Assay for Lenvatinib Using Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry With Clinical Application in Patients With Hepatocellular Carcinoma
A Broad Range High-Throughput Assay for Lenvatinib Using Ultra-High Performance Liquid Chromatography Coupled to Tandem Mass Spectrometry With Clinical Application in Patients With Hepatocellular Carcinoma
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DOI：
10.1097/ftd.0000000000000872
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发表时间：
2021-10-01
影响因子：
2.5
通讯作者：
Itoh, Hiroki
中科院分区：
文献类型：
--
作者：
Sueshige, Yoshio;Shiraiwa, Ken;Itoh, Hiroki
背景：根据Reflect试验的结果，越来越多的人选择lenvatinib作为不能切除的肝细胞癌的一线治疗方法。然而，因不良反应而早期停用伦瓦替尼的情况经常发生。因此，Lenvatinib是一种难以在临床环境中使用的药物。其中一个原因是，尽管个体间有很高的变异性，但兰瓦替尼的剂量主要由体重决定。为了克服这一问题，提出了一种基于群体药代动力学(PPK)模型的肝细胞癌患者给药方案。本研究的目的是建立一种高通量的超高效液相色谱-串联质谱联用(UHPLC-MS/MS)定量方法，用于未来肝细胞癌患者的PPK分析。方法：采用96孔板进行简单的固相萃取，采用电喷雾正电离方式，采用UHPLCMS/MS联用技术对利凡替尼进行分析。结果：新方法符合美国食品和药物管理局关于生物分析方法验证指南的要求。在0.2~1000 ng/mL浓度范围内线性关系良好。平均回收率为98.63+/-4.55%(平均+/-SD)。所有质控水平的精密度均在6.05%以下，准确度均在12.96%以内。基质效应在103.33%~134.61%之间变化。该方法已成功地用于6例接受雷瓦替尼治疗的肝癌患者的血药浓度测定。结论：建立了高通量高效液相色谱-串联质谱法测定人血浆中雷瓦替尼浓度的方法。该方法可用于临床上接受Lenvatinib治疗的患者的PPK分析。
Background: Lenvatinib is increasingly being selected as the first-line treatment for unresectable hepatocellular carcinoma (HCC) based on the results of the REFLECT trial. However, early discontinuation of lenvatinib because of adverse effects is a frequent occurrence. Hence, lenvatinib is a difficult drug for use in the clinical setting. One of the causes is that the dose of lenvatinib is mainly determined by body weight alone, despite high interindividual variability. To overcome this problem, a dosing regimen of lenvatinib based on a population pharmacokinetic (PPK) model for HCC patients is proposed. The aim of this study was to develop a high-throughput quantification method for lenvatinib using ultra-high performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS) that can be applied to a PPK analysis of HCC patients in the future. Methods: After a simple solid-phase extraction step using a 96-well plate, lenvatinib was analyzed by UHPLC-MS/MS in a positive electrospray ionization mode. Results: The novel method fulfilled the requirements of the US Food and Drug Administration guidance on bioanalytical method validation. The calibration curve was linear over the 0.2-1000 ng/mL concentration range. The average recovery rate was 98.63 +/- 4.55% (mean +/- SD). The precision was below 6.05%, and the accuracy was within 12.96% for all quality control levels. The matrix effect varied between 103.33% and 134.61%. This assay was successfully applied to the measurement of plasma concentrations in 6 HCC patients receiving lenvatinib. Conclusions: A novel high-throughput UHPLC-MS/MS assay for quantification of lenvatinib in human plasma was successfully developed. This method can be applied to PPK analysis for patients receiving lenvatinib in the clinical setting.