Zhao Jing, Yan Dongming, Li Yue, Xu Xiaoqing, Li Fengling, Zhang Shuang, Jin Jingyi, Qiu Furong
Laboratory of Clinical Pharmacokinetics, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201213, China.
Laboratory of Clinical Pharmacokinetics, Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201213, China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Apr 15;1237:124100. doi: 10.1016/j.jchromb.2024.124100. Epub 2024 Mar 26.
Interindividual exposure differences have been identified in oral targeted antineoplastic drugs (OADs) owing to the pharmacogenetic background of the patients and their susceptibility to multiple factors, resulting in insufficient efficacy or adverse effects. Therapeutic drug monitoring (TDM) can prevent sub-optimal concentrations of OADs and improve their clinical treatment. This study aimed to develop and validate an LC-MS/MS method for the simultaneous quantification of 11 OADs (gefitinib, imatinib, lenvatinib, regorafenib, everolimus, osimertinib, sunitinib, tamoxifen, lapatinib, fruquintinib and sorafenib) and 2 active metabolites (N-desethyl sunitinib and Z-endoxifen) in human plasma. Protein precipitation was used to extract OADs from the plasma samples. Chromatographic separation was performed using an Eclipse XDB-C18 (4.6 × 150 mm, 5 μm) column with a gradient elution of the mobile phase composed of 2 mM ammonium acetate with 0.1 % formic acid in water (solvent A) and methanol (solvent B) at a flow rate of 0.8 mL/min. Mass analysis was performed using positive ion mode electrospray ionization in multiple-reaction monitoring mode. The developed method was validated following FDA bioanalytical guidelines. The calibration curves were linear over the range of 2-400 ng/mL for gefitinib, imatinib, lenvatinib, regorafenib, and everolimus; 1-200 ng/mL for osimertinib, sunitinib, N-desethyl sunitinib, tamoxifen, and Z-endoxifen; and 5-1000 ng/mL for lapatinib, fruquintinib, and sorafenib, with all coefficients of correlation above 0.99. The intra- and inter-day imprecision was below 12.81 %. This method was successfully applied to the routine TDM of gefitinib, lenvatinib, regorafenib, osimertinib, fruquintinib, and sorafenib to optimize the dosage regimens.
由于患者的药物遗传学背景及其对多种因素的易感性，口服靶向抗肿瘤药物（OAD）存在个体间暴露差异，导致疗效不足或出现不良反应。治疗药物监测（TDM）可以避免OAD浓度未达最佳水平，并改善其临床治疗效果。本研究旨在开发并验证一种液相色谱-串联质谱（LC-MS/MS）方法，用于同时定量测定人血浆中的11种OAD（吉非替尼、伊马替尼、仑伐替尼、瑞戈非尼、依维莫司、奥希替尼、舒尼替尼、他莫昔芬、拉帕替尼、呋喹替尼和索拉非尼）以及2种活性代谢物（N-去乙基舒尼替尼和Z-4-羟基他莫昔芬）。采用蛋白沉淀法从血浆样本中提取OAD。色谱分离使用Eclipse XDB-C18（4.6×150 mm，5μm）色谱柱，以含0.1%甲酸的2 mM醋酸铵水溶液（溶剂A）和甲醇（溶剂B）作为流动相进行梯度洗脱，流速为0.8 mL/min。采用正离子模式电喷雾电离在多反应监测模式下进行质谱分析。所开发的方法按照美国食品药品监督管理局（FDA）生物分析指南进行验证。吉非替尼、伊马替尼、仑伐替尼、瑞戈非尼和依维莫司的校准曲线在2-400 ng/mL范围内呈线性；奥希替尼、舒尼替尼、N-去乙基舒尼替尼、他莫昔芬和Z-4-羟基他莫昔芬的校准曲线在1-200 ng/mL范围内呈线性；拉帕替尼、呋喹替尼和索拉非尼的校准曲线在5-1000 ng/mL范围内呈线性，所有相关系数均高于0.99。日内和日间精密度均低于12.81%。该方法已成功应用于吉非替尼、仑伐替尼、瑞戈非尼、奥希替尼、呋喹替尼和索拉非尼的常规TDM，以优化给药方案。
