Optimization of a sensitive and reliable UPLC-MS/MS method to simultaneously quantify almonertinib and HAS-719 and its application to study the interaction with nicardipine

• Published in: Pharmaceutical biology 2024-12, Vol.62 (1), p.874-881
• Main Authors: Chen, Dongxin, Chen, Jie, Shen, Yuxin, Chen, Xiaohai, Xia, Hailun, Liu, Ya-Nan, Xu, Ren-Ai
• Format: Article
• Language: English
• Subjects: Almonertinib; Animals; Chromatography, High Pressure Liquid - methods; Drug interaction; Drug Interactions; HAS-719; Liquid chromatography; Liquid Chromatography-Mass Spectrometry; Male; Mass spectroscopy; Metabolism; Metabolites; Microsomes; Microsomes, Liver - metabolism; nicardipine; Nicardipine - pharmacology; Pharmacokinetics; rat plasma; Rats; Rats, Sprague-Dawley; Reproducibility of Results; Tandem Mass Spectrometry - methods; UPLC-MS/MS
• ISSN: 1388-0209; 1744-5116; 1744-5116
• DOI: 10.1080/13880209.2024.2425648

Almonertinib is primarily metabolized by CYP3A4, so it could interact with a variety of drugs metabolized by CYP3A4, leading to the changes of systemic exposure. For the purpose of this experiment, an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) assay with accuracy and simplicity was optimized and fully validated for the simultaneous quantitative determination of almonertinib and its metabolite HAS-719, and drug-drug interactions (DDI) between almonertinib and nicardipine and was researched. Detection of analytes was achieved by UPLC-MS/MS coupled with multiple reaction monitoring (MRM) in the positive ion mode with ion transitions of 526.01 → 72.04 for almonertinib, 512.18 → 455.08 for HAS-719 and 447.16 → 128.11 for IS, respectively. There was favourable linearity in the 0.5-200 ng/mL calibration range for almonertinib and 0.5-100 ng/mL for HAS-719. The lower limit of quantification (LLOQ) for both analytes was 0.5 ng/mL. The precision, accuracy, stability, matrix effect and extraction recovery required for methodological validation were consistent with the requirements of FDA guideline. Then, the UPLC-MS/MS assay was employed successfully on the interactions of almonertinib and nicardipine and . The half-maximal inhibitory concentration (IC ) was 1.19 μM in rat liver microsomes (RLM), where nicardipine inhibited the metabolism of almonertinib with a mixed inhibitory mechanism. In pharmacokinetic experiments of rats, it was observed that nicardipine could significantly alter the pharmacokinetic profiles of almonertinib, including AUC AUC and C , but had no effect on the metabolism of HAS-719. According to the findings, it was indicated that nicardipine could inhibit the metabolism of almonertinib .