Pharmacokinetics comparison of aumolertinib, osimertinib, gefitinib and their major metabolites in mouse model and NSCLC patients

The tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR), such as osimertinib and gefitinib, aumolertinib have been widely used in EGFR mutation‐positive non‐small cell lung cancer (NSCLC) patients. However, the discrepancy of pharmacokinetic features and distributions in important tissues between these EGFR‐TKIs remains obscure. In this study, an ultra‐performance liquid chromatography‐tandem mass spectrometry (UPLC‐MS/MS) method with specificity and accuracy was established. After a single equivalent dose ratio or equal dose gavage, aumolertinib displayed the shortest elimination half‐life time ( t 1/2 ), while it showed the largest area under the concentration–time curve in mouse plasma and bone marrow among these 3 EGFR‐TKIs. Furthermore, at the time of reaching maximum concentration ( t max ) after single equivalent dose ratio gavage, the concentrations of aumolertinib were significantly higher than that of osimertinib and gefitinib in 9 important tissues of mice. Moreover, after single oral administration, aumolertinib displayed the highest concentration in plasma samples from EGFR mutation‐positive NSCLC patients. Collectively, our findings manifest that the bioavailability and tissue distribution features of aumolertinib are superior to those of osimertinib and gefitinib, providing a pharmacokinetic basis for the clinical application of aumolertinib and the development of next‐generation EGFR‐TKIs.