由于患者的药物遗传学背景及其对多种因素的易感性,已在口服靶向抗肿瘤药物(OADs)中确定了个体间暴露差异。导致疗效不足或不良反应。治疗药物监测(TDM)可以预防OAD的次优浓度并改善其临床治疗。本研究旨在开发和验证同时定量11种OAD的LC-MS/MS方法(吉非替尼,伊马替尼,lenvatinib,Regorafenib,依维莫司,奥希替尼,舒尼替尼,他莫昔芬,拉帕替尼,人血浆中的氟喹替尼和索拉非尼)和2种活性代谢物(N-去乙基舒尼替尼和Z-内西芬)。使用蛋白质沉淀从血浆样品中提取OAD。使用EclipseXDB-C18(4.6×150mm,5μm)的色谱柱,其中以0.8mL/min的流速对由2mM乙酸铵与在水(溶剂A)和甲醇(溶剂B)中的0.1%甲酸组成的流动相进行梯度洗脱。在多反应监测模式下使用正离子模式电喷雾电离进行质量分析。所开发的方法根据FDA生物分析指南进行验证。吉非替尼的校准曲线在2-400ng/mL范围内呈线性关系,伊马替尼,lenvatinib,Regorafenib,和依维莫司;奥希替尼1-200ng/mL,舒尼替尼,N-去乙基舒尼替尼,他莫昔芬,和Z-endoxifen;拉帕替尼5-1000ng/mL,fruquintinib,还有索拉非尼,所有相关系数都在0.99以上。日内和日间不准确性低于12.81%。该方法成功应用于吉非替尼常规TDM,lenvatinib,Regorafenib,奥希替尼,fruquintinib,和索拉非尼优化给药方案。
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.