Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China; University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 501 Haike Road, Shanghai 201203, China.
J Chromatogr B Analyt Technol Biomed Life Sci. 2022 May 1;1197:123231. doi: 10.1016/j.jchromb.2022.123231. Epub 2022 Mar 24.
The combination of two or more drugs in a clinical setting has an impact in pharmacokinetics, drug efficacy and safety, and the study of these interactions has attracted considerable attention over the last years. In the present study, we have developed a LC-MS/MS method for the sensitive and reliable quantification of almonertinib and its active metabolite HAS-719. Further, we investigated the effects of their pharmacokinetics in humans by using modulators of CYP3A, an almonertinib-metabolizing enzyme. Analytes were extracted from plasma samples via acetonitrile-induced protein precipitation and separated on a BEH C18 column using ammonium acetate with formic acid and acetonitrile as the mobile phase. Electrospray ionization in positive ion mode and multiple reaction monitoring were used to monitor the ion transitions at m/z 526 → 411 and 512 → 423. Validation was performed in the range 0.500 to 500 ng/mL for both the analytes of interest according to the guidelines of the U.S. Food and Drug Administration and European Medicines Agency, sufficient to account for variations in plasma concentrations caused by the presence of CYP3A modulators. The selectivity, precision, accuracy, recovery and matrix effect of this method were all within acceptable limits of bioanalytics. The interference of CYP3A modulators itraconazole and rifampicin with the analytes, and the mutual interference between the analytes were also investigated producing acceptable results. The method herein described was successfully applied for the pharmacokinetics evaluation of almonertinib in healthy subjects exposed to a single dose of almonertinib (110 mg), with or without itraconazole or rifampicin.
在临床环境中，两种或多种药物的联合使用会对药代动力学、药物疗效和安全性产生影响，近年来，这些相互作用的研究引起了相当大的关注。在本研究中，我们开发了一种 LC-MS/MS 方法，用于灵敏和可靠地定量分析阿美替尼及其活性代谢物 HAS-719。此外，我们通过使用 CYP3A 的调节剂来研究它们在人体内的药代动力学效应，CYP3A 是阿美替尼的代谢酶。通过乙腈诱导的蛋白沉淀从血浆样品中提取分析物，然后在 BEH C18 柱上用含甲酸和乙腈的乙酸铵作为流动相进行分离。采用正离子模式电喷雾电离和多反应监测监测 m/z 526→411 和 512→423 的离子跃迁。根据美国食品和药物管理局和欧洲药品管理局的指南，对两种感兴趣的分析物在 0.500 至 500ng/mL 的范围内进行了验证，足以说明 CYP3A 调节剂存在时引起的血浆浓度变化。该方法的选择性、精密度、准确度、回收率和基质效应均在生物分析可接受范围内。还研究了 CYP3A 调节剂伊曲康唑和利福平与分析物的相互干扰，以及分析物之间的相互干扰，结果令人满意。本文描述的方法成功地应用于健康受试者单次给予阿美替尼（110mg），并联合或不联合伊曲康唑或利福平时的阿美替尼药代动力学评价。
