Researchers may have established an accurate ultraperformance liquid chromatography–tandem mass spectrometry (UPLC-MS/MS) method for comparing the pharmacokinetic properties of three epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and their major metabolites in mouse models and patients with non–small cell lung cancer (NSCLC), according to a recent study published by Bailleul et al in the National Science Review. The findings could provide a pharmacokinetic basis for the clinical application of aumolertinib and the development of next-generation EGFR TKIs.
Study Methods and Results
In the study, the researchers validated the novel UPLC-MS/MS method for specificity, linearity, precision and accuracy, matrix effect and extraction recovery, stability, and dilution integrity. They then applied the UPLC-MS/MS method for simultaneous quantification of aumolertinib, osimertinib, and gefitinib as well as their major metabolites in mice plasma, bone marrow, lung, brain, liver, pancreas, spleen, kidney, large intestine, and EGFR mutation–positive plasma from patients with NSCLC.
The researchers discovered that following single equivalent dose ratio or equal dose gavage, aumolertinib displayed the shortest elimination half-life time, while showing the largest area under the concentration–time curve (AUC) in mouse plasma and bone marrow among the three EGFR TKIs.
Further, at the time to reach maximum concentration after single equivalent dose ratio gavage, the concentrations of aumolertinib were significantly higher compared with those of osimertinib and gefitinib in nine important tissues of mice. Notably, after single oral administration, aumolertinib demonstrated the highest concentration in plasma samples from patients with EGFR mutation–positive NSCLC.
“[S]everal clinical trials have demonstrated that combining aumolertinib with other therapies (eg antiangiogenic agents, other EGFR-TKIs, chemotherapy, and radiotherapy) display a variety of benefits such as improved therapeutic efficacy and prolonged progression free survival for [patients with] EGFR mutation–positive NSCLC compared to monotherapy,” the study authors emphasized.
Conclusions
In conclusion, an accurate and effective UPLC-MS/MS method was developed to simultaneously quantify aumolertinib, osimertinib, gefitinib, and their major metabolites.
The researchers underscored that by using the novel UPLC-MS/MS method, aumolertinib exhibited greater pharmacokinetic profiles compared with the other two EGFR TKIs. Specifically, aumolertinib and its major metabolite, HAS719, showed the highest AUC in mouse plasma and bone marrow. Additionally, the concentrations of aumolertinib in nine important tissues of mice were higher compared with those of osimertinib and gefitinib, and the plasma concentration of aumolertinib in patients with EGFR mutation–positive NSCLC was also found to be the highest after administration of a single equivalent dose ratio.
Together, the findings could help improve the understanding of the clinical use of aumolertinib and provide a pharmacokinetic basis for the research and development of next-generation EGFR TKIs.
Disclosure: For full disclosures of the study authors, visit academic.oup.com.
