Simultaneous determination of almonertinib and its active metabolite HAS-719 in human plasma by LC-MS/MS: Evaluation of pharmacokinetic interactions

化学 蛋白质沉淀 药代动力学 色谱法 分析物 活性代谢物 治疗药物监测 代谢物 选择性反应监测 电喷雾电离 甲酸 质谱法 药理学 串联质谱法 生物化学 医学
作者
Lu Liu,Le Yang,Wei Li,Xiaoyan Chen
出处
期刊:Journal of Chromatography B [Elsevier BV]
卷期号:1197: 123231-123231 被引量:7
标识
DOI:10.1016/j.jchromb.2022.123231
摘要

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.
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