Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Shenyang 110004, China.
Shengjing Hospital of China Medical University, No. 36, Sanhao Street, Shenyang 110004, China.
J Pharm Biomed Anal. 2022 Apr 1;212:114517. doi: 10.1016/j.jpba.2021.114517. Epub 2021 Dec 9.
In this study, an ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed to simultaneously detect 15 targeted anti-cancer drugs: aletinib, afatinib, apatinib, icotinib, dasatinib, erlotinib, gefitinib, crizotinib, lapatinib, regorafenib, ceritinib, sorafenib, vemurafenib, imatinib, and N-desmethyl imatinib. Plasma samples were processed using a new magnetic solid phase extraction technique to extract each drug. The 15 analytes and four isotope internal standards were separated using an Agilent Eclipse XDB-C18 column (50.0 × 2.1 mm, 1.7 µm) with water containing 0.1% formic acid and acetonitrile as the mobile phase. The method verification included specificity, calibration curves, carryover, accuracy, crosstalk, precision, stability, recovery, dilution integrity, and matrix effects. The results showed that the developed UPLC-MS/MS method met the requirements of the U.S. Food and Drug Administration guidelines for methodological validation and could be used to monitor plasma concentrations. The response function was established for concentration range of 2.5-2500.0 ng/mL for aletinib, afatinib, apatinib, icotinib, dasatinib, crizotinib, regorafenib, vemurafenib, and N-desmethyl imatinib and 10.0-10,000.0 ng/mL for erlotinib, ceritinib, imatinib, sorafenib, gefitinib, and lapatinib, with a coeffificient of correlation of > 0.9977 for all the compounds. The precision and accuracy of all the analytes were < 6.88% and 5.29%, respectively. The percentage recovery and matrix effect of all the analytes were 91.3-103% and 93.8-102% for three QC concentrations levels. The recovery and matrix effect for all the ISs ranged from 93.7% to 98.8% and 94.6-101%. Meanwhile, we also found that the plasma concentrations of these targeted anti-cancer drugs showed large individual differences, which is not conducive to the treatment of tumors. Therefore, therapeutic drug monitoring (TDM) of these 15 targeted anti-cancer drugs is necessary, and this method could be used for TDM and exploration of pharmacokinetics of the aforementioned 15 targeted anti-cancer drugs.
在这项研究中，建立了一种超高效液相色谱-串联质谱（UPLC-MS/MS）方法，用于同时检测 15 种靶向抗癌药物：阿来替尼、阿法替尼、阿帕替尼、伊可替尼、达沙替尼、厄洛替尼、吉非替尼、克唑替尼、拉帕替尼、regorafenib、塞瑞替尼、索拉非尼、维莫非尼、伊马替尼和 N-去甲基伊马替尼。采用一种新的磁性固相萃取技术处理血浆样品，以提取每种药物。使用 Agilent Eclipse XDB-C18 柱（50.0×2.1mm，1.7μm），以含有 0.1%甲酸的水和乙腈作为流动相，分离 15 种分析物和 4 种同位素内标。方法验证包括专属性、校准曲线、残留、准确度、串扰、精密度、稳定性、回收率、稀释完整性和基质效应。结果表明，所建立的 UPLC-MS/MS 方法符合美国食品和药物管理局方法验证指南的要求，可用于监测血浆浓度。建立了浓度范围为 2.5-2500.0ng/mL 的阿来替尼、阿法替尼、阿帕替尼、伊可替尼、达沙替尼、克唑替尼、regorafenib、维莫非尼和 N-去甲基伊马替尼，以及浓度范围为 10.0-10000.0ng/mL 的厄洛替尼、塞瑞替尼、伊马替尼、索拉非尼、吉非替尼和拉帕替尼的响应函数，所有化合物的相关系数均>0.9977。所有分析物的精密度和准确度均<6.88%和 5.29%。所有分析物在三个 QC 浓度水平的回收率和基质效应分别为 91.3-103%和 93.8-102%。所有 IS 的回收率和基质效应范围为 93.7%-98.8%和 94.6-101%。同时，我们还发现这些靶向抗癌药物的血浆浓度个体差异较大，不利于肿瘤的治疗。因此，有必要对这些 15 种靶向抗癌药物进行治疗药物监测（TDM），该方法可用于上述 15 种靶向抗癌药物的 TDM 和药代动力学研究。
