Department of Clinical Pharmacy, Oita University Hospital; and.
Department of Gastroenterology, Oita University Faculty of Medicine, Yufu-shi, Oita, Japan .
Ther Drug Monit. 2021 Oct 1;43(5):664-671. doi: 10.1097/FTD.0000000000000872.
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.
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.
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.
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.
基于 REFLECT 试验的结果，仑伐替尼越来越多地被选为不可切除肝细胞癌（HCC）的一线治疗药物。然而，由于不良反应而提前停止仑伐替尼治疗的情况经常发生。因此，仑伐替尼在临床应用中是一种棘手的药物。其中一个原因是仑伐替尼的剂量主要仅根据体重来确定，尽管个体间差异很大。为了解决这个问题，提出了一种基于 HCC 患者群体药代动力学（PPK）模型的仑伐替尼剂量方案。本研究的目的是开发一种用于 HCC 患者 PPK 分析的高效液相色谱-串联质谱（UHPLC-MS/MS）高通量仑伐替尼定量方法。
采用 96 孔板固相萃取法进行简单的样品前处理后，采用正电喷雾电离模式的 UHPLC-MS/MS 进行仑伐替尼分析。
该新方法满足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。校准曲线在 0.2-1000ng/mL 浓度范围内呈线性。平均回收率为 98.63±4.55%（平均值±SD）。所有质控水平的精密度均低于 6.05%，准确度均在 12.96%以内。基质效应在 103.33%-134.61%之间变化。该方法成功应用于 6 例接受仑伐替尼治疗的 HCC 患者的血浆浓度测量。
成功开发了一种用于人血浆中仑伐替尼定量的新型高通量 UHPLC-MS/MS 测定法。该方法可应用于临床接受仑伐替尼治疗的患者的 PPK 分析。
