National Clinical Drug Monitoring Center, Department of Pharmacy, Hebei Province General Center, Shijiazhuang 050051, China.
Hebei Provincial Key Laboratory of Basic Medicine for Diabetes, Shijiazhuang 050057, China.
Molecules. 2022 Jul 13;27(14):4474. doi: 10.3390/molecules27144474.
The third-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), osimertinib, aumolertinib, and furmonertinib represent a new treatment option for patients with EGFR p.Thr790 Met (T790 M)-mutated non-small cell lung cancer (NSCLC). Currently, there are no studies reporting the simultaneous quantification of these three drugs. A simple ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed and validated for the simultaneous quantitative determination of osimertinib, aumolertinib, and furmonertinib concentrations in human plasma, and it was applied for therapeutic drug monitoring (TDM). Plasma samples were processed using the protein precipitation method (acetonitrile). A positive ion monitoring mode was used for detecting analytes. D-Sorafenib was utilized as the internal standard (IS), and the mobile phases were acetonitrile (containing 0.1% formic acid) and water with gradient elution on an XSelect HSS XP column (2.1 mm × 100.0 mm, 2.5 µm, Waters, Milford, MA, USA) at a flow rate of 0.5 mL·min. The method's selectivity, precision (coefficient of variation of intra-day and inter-day ≤ 6.1%), accuracy (95.8-105.2%), matrix effect (92.3-106.0%), extraction recovery, and stability results were acceptable according to the guidelines. The linear ranges were 5-500 ng·mL, 2-500 ng·mL, and 0.5-200 ng·mL for osimertinib, aumolertinib, and furmonertinib, respectively. The results show that the method was sensitive, reliable, and simple and that it could be successfully applied to simultaneously determine the osimertinib, aumolertinib, and furmonertinib blood concentrations in patients. These findings support using the method for TDM, potentially reducing the incidence of dosing blindness and adverse effects due to empirical dosing and inter-patient differences.
第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKIs），奥希替尼、阿美替尼和伏美替尼，为 EGFR p.Thr790 Met（T790M）突变的非小细胞肺癌（NSCLC）患者提供了新的治疗选择。目前，尚无研究报告同时定量检测这三种药物。本研究建立并验证了一种简单的超高效液相色谱-串联质谱法（UPLC-MS/MS），用于同时定量测定人血浆中的奥希替尼、阿美替尼和伏美替尼浓度，并将其应用于治疗药物监测（TDM）。采用蛋白沉淀法（乙腈）处理血浆样品。采用正离子监测模式检测分析物。D-索拉非尼作为内标（IS），流动相为乙腈（含 0.1%甲酸）和水，在 XSelect HSS XP 柱（2.1mm×100.0mm，2.5µm，Waters，Milford，MA，USA）上采用梯度洗脱，流速为 0.5mL·min。根据指南，该方法的选择性、精密度（日内和日间变异系数≤6.1%）、准确度（95.8-105.2%）、基质效应（92.3-106.0%）、提取回收率和稳定性结果均可接受。奥希替尼、阿美替尼和伏美替尼的线性范围分别为 5-500ng·mL、2-500ng·mL和 0.5-200ng·mL。结果表明，该方法灵敏、可靠、简单，可成功用于同时测定患者奥希替尼、阿美替尼和伏美替尼的血药浓度。这些发现支持使用该方法进行 TDM，可能会降低因经验性给药和个体间差异导致的剂量盲目性和不良反应的发生率。
