This study is led by Dr Yongsheng Li, Dr Dairong Li, Dr Huakan Zhao (Department of Medical Oncology, Chongqing University Cancer Hospital) and PhD student Ran Ren (Chongqing University Cancer Hospital, School of Medicine, Chongqing University).

Lung cancer is the primary cause of cancer-related deaths globally, and the tyrosine kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR), such as aumolertinib, osimertinib and gefitinib, have been widely used in EGFR mutation-positive non-small cell lung cancer (NSCLC) patients.

This work presents important findings on the pharmacokinetics of EGFR-TKIs.

The researchers established a specific and accurate UPLC-MS/MS method to compare the pharmacokinetic properties of these 3 EGFR-TKIs and their major metabolites in mouse models and NSCLC patients, providing a pharmacokinetic basis for the clinical application of aumolertinib and development of next- generation EGFR-TKIs.

Firstly, the UPLC-MS/MS method was validated for specificity, linearity, precision and accuracy, matrix effect and extraction recovery, stability and dilution integrity.

Then, the reliable UPLC-MS/MS method was applied for simultaneous quantification of aumolertinib, osimertinib, gefitinib and their major metabolites in mice plasma, bone marrow, lung, brain, liver, pancreas, spleen, kidney, large intestine and EGFR mutation- positive NSCLC patients' plasma.

The team found that after 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 (AUC) in mouse plasma and bone marrow among these 3 EGFR-TKIs.

Furthermore, at the time to reach 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.

More importantly, after single oral administration, aumolertinib displayed the highest concentration in plasma samples from EGFR mutation-positive NSCLC patients.

The authors also noted that, “several 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 ( PFS), for EGFR mutations positive NSCLC patients, compared to monotherapy.”

In conclusion, an accurate and effective UPLC-MS/MS method was developed to simultaneously quantify aumolertinib, osimertinib, gefitinib, and their major metabolites.

By using this method, the team found that aumolertinib exhibited better pharmacokinetic profiles compared to 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 9 important tissues of mice were higher than those of osimertinib and gefitinib.

Furthermore, the plasma concentration of aumolertinib in EGFR mutation-positive NSCLC patients was also found to be the highest after administration of a single equivalent dose ratio.

Together these findings contribute to a better understanding of the clinical use of aumolertinib, and provide a pharmacokinetic basis for the research and development of next-generation EGFR-TKIs.

Source: Sichuan International Medical Exchange and Promotion Association