An Liquid Chromatography-Tandem Mass Spectrometry Method for the Simultaneous Determination of Afatinib, Alectinib, Ceritinib, Crizotinib, Dacomitinib, Erlotinib, Gefitinib, and Osimertinib in Human Serum
An Liquid Chromatography-Tandem Mass Spectrometry Method for the Simultaneous Determination of Afatinib, Alectinib, Ceritinib, Crizotinib, Dacomitinib, Erlotinib, Gefitinib, and Osimertinib in Human Serum
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液相色谱-串联质谱法同时测定人血清中的阿法替尼、艾乐替尼、塞瑞替尼、克唑替尼、达克替尼、厄洛替尼、吉非替尼和奥希替尼
DOI：
10.1097/ftd.0000000000000895
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发表时间：
2021
影响因子：
2.5
通讯作者：
Toda Takaki
中科院分区：
文献类型：
--
作者：
Mukai Yuji;Wakamoto Azusa;Hatsuyama Tae;Yoshida Tatsunari;Sato Hideki;Fujita Akihisa;Inotsume Nobuo;Toda Takaki
背景：常规治疗药物监测是合理使用表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）和间变性淋巴瘤激酶（ALK）抑制剂的一种有前途的方法。本研究的目的是开发和验证同时测定5种EGFR-TKI（阿法替尼、达克替尼、厄洛替尼、吉非替尼和奥希替尼）和3种ALK抑制剂（阿来替尼、塞瑞替尼和克唑替尼）的液相色谱-串联质谱（LC-MS/MS）方法。方法：用100 μL含内标物的1%氨水稀释100 mL等份血清，然后使用支持液体萃取法纯化。采用正离子模式进行LC-MS/MS分析，并根据已发表的指南对方法进行验证。批内和批间准确度分别为90.7%~ 110.7%和94.7%~ 107.6%。所有试验内和试验间不精密度值均≤ 10.1%。本研究中检查的EGFR-TKI和ALK抑制剂（奥希替尼除外，其可在冰上储存至少5小时）在室温下稳定3小时。对于内标物归一化基质因子，平均回收率和变异系数百分比值范围分别为54%-112%和1.7%-11.7%。该方法成功测定了临床样本中阿法替尼、alectinib、厄洛替尼、吉非替尼和奥希替尼的血清浓度。激酶抑制剂的血清水平一致地反映了那些在以前的studies.Conclusions报告：LC-MS/MS方法适用于同时测定5 EGFR-TKI和3 ALK抑制剂在血清中的开发和验证。新开发的方法能够测定临床样品中检查的8种目标药物中的5种。但是，需要对大量的临床样本进行分析，以验证该方法的有效性。
Background:Routine therapeutic drug monitoring is a promising approach for the rational use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and anaplastic lymphoma kinase (ALK) inhibitors. The purpose of this study was to develop and validate a liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of 5 EGFR-TKIs (afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib) and 3 ALK inhibitors (alectinib, ceritinib, and crizotinib).Methods:A 100-mL aliquot of serum was diluted with 100 μL of 1% aqueous ammonia containing internal standards and then purified using the supported liquid extraction method. LC-MS/MS was conducted in positive ionization mode, and the method was validated according to published guidelines.Results:Calibration curves were linear across concentration ranges examined. The intra-and interassay accuracies were 90.7%–110.7% and 94.7%–107.6%, respectively. All intra-and interassay imprecision values were≤ 10.1%. The EGFR-TKIs and ALK inhibitors examined in this study, except osimertinib, which could be stored on ice for at least 5 hours, were stable at room temperature for 3 hours. For the internal standard–normalized matrix factors, the mean recovery and percent coefficient of variation values ranged between 54%–112% and 1.7%–11.7%, respectively. This method successfully determined serum concentrations of afatinib, alectinib, erlotinib, gefitinib, and osimertinib in clinical samples. Serum levels of kinase inhibitors consistently reflected those reported in previous studies.Conclusions:An LC-MS/MS method suitable for the simultaneous determination of 5 EGFR-TKIs and 3 ALK inhibitors in serum was developed and validated. The newly developed method enabled the determination of 5 of 8 target drugs examined in clinical samples. However, a large number of clinical samples need to be analyzed to verify the usefulness of the method.