Tang Peng-Fei, Bao Su-Su, Gao Nan-Yong, Shao Chuan-Feng, Xie Wei-Fei, Wu Xue-Meng, Zhao Le-Ping, Xiao Zhong-Xiang
Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China.
Department of Pharmacology, School of Pharmacy of Wenzhou Medical University, Wenzhou, China.
Front Pharmacol. 2022 Jul 22;13:960311. doi: 10.3389/fphar.2022.960311. eCollection 2022.
Almonertinib was approved for the first-line treatment of advanced NSCLC patients with EGFR-TKI-sensitive genetic mutations by National Medical Products Administration (NMPA) in 2021.The purpose of this study was to establish and validate a fast, accurate, stable and facile ultra-performance liquid chromatography-tandem mass spectrometry method for the quantification of almonertinib in rat plasma, it was employed to explore the effect of Paxlovid on the pharmacokinetics of almonertinib in rats. Zanubrutinib was used as an internal standard (IS), and the plasma samples were prepared by the protein precipitation method using acetonitrile. Chromatographic separation was carried out on a Shimadzu LC-20AT ultra-performance liquid chromatography system using a Shim-pack velox C18 (2.1× 50 mm, 2.7 μM) column. The mobile phase consisted of methanol and 0.1% formic acid-water. Mass spectrum analysis was executed using Shimadzu 8040 Triple quadrupole mass spectrometry. The precursor and product ions of the analyte and internal standard were detected in multiple reaction monitoring (MRM) mode. The typical fragment ions were for almonertinib and for zanubrutinib (IS). The method was validated to have good linearity for quantifying almonertinib in rat plasma from 0.1-1000 ng/ml (R = 0.999), and the LLOQ was 0.1 ng/ml. The validity of this method was sufficiently verified for selectivity, specificity, extraction recovery, matrix effect, accuracy, precision and stability. The validated UHPLC-MS/MS method was successfully applied to the drug interaction study of almonertinib with Paxlovid in rats. Paxlovid significantly inhibits the metabolism of almonertinib and increased the exposure of almonertinib. This study can help us to understand the metabolic profile of almonertinib better, and further human trials should be conducted to validate the results.
2021年，国家药品监督管理局（NMPA）批准阿美替尼用于一线治疗具有EGFR-TKI敏感基因突变的晚期非小细胞肺癌（NSCLC）患者。本研究的目的是建立并验证一种快速、准确、稳定且简便的超高效液相色谱-串联质谱法，用于定量大鼠血浆中的阿美替尼，并探讨帕罗韦德对大鼠体内阿美替尼药代动力学的影响。以泽布替尼作为内标（IS），血浆样品采用乙腈蛋白沉淀法制备。色谱分离在岛津LC-20AT超高效液相色谱系统上进行，使用Shim-pack velox C18（2.1×50 mm，2.7μm）色谱柱。流动相由甲醇和0.1%甲酸水组成。质谱分析采用岛津8040三重四极杆质谱仪进行。在多反应监测（MRM）模式下检测分析物和内标的前体离子和产物离子。阿美替尼的典型碎片离子为 ，泽布替尼（内标）的典型碎片离子为 。该方法在0.1 - 1000 ng/ml大鼠血浆中定量阿美替尼具有良好的线性（R = 0.999），最低定量限（LLOQ）为0.1 ng/ml。该方法在选择性、特异性、提取回收率、基质效应、准确性、精密度和稳定性方面的有效性得到了充分验证。经过验证的超高效液相色谱-串联质谱法成功应用于阿美替尼与帕罗韦德在大鼠体内的药物相互作用研究。帕罗韦德显著抑制阿美替尼的代谢并增加了阿美替尼的暴露量。本研究有助于我们更好地了解阿美替尼的代谢概况，应进一步开展人体试验以验证结果。
