An ultra-fast validated green UPLC-MS/MS method for the quantification of osimertinib in human liver microsomes: Screening for ADME parameters and in vitro metabolic stability

Osimertinib (Tagrisso, AstraZeneca Pharmaceuticals) is the inaugural third-generation irreversible EGFR-TKI that specifically targets both the EGFR T790M resistant mutation and EGFR-TKI-sensitizing mutations. On September 25, 2024, the Food and Drug Administration authorized osimertinib (OSM) for adult patients with locally advanced, unresectable (stage III) non-small cell lung cancer (NSCLC). The target of this work was to establish a fast, accurate, environmentally friendly, and highly sensitive UPLC-MS/MS methodology for detecting OSM levels in human liver microsomes (HLMs). The separation of OSM and zanubrutinib (ZNB) was accomplished utilizing a C8 column and an isocratic mobile phase. The linearity of the OSM calibration curve spanned from 1 to 3,000 ng mL-1. The AGREE score of 0.76 validates the efficacy of the current approach. The brief in vitro half-life (23.72 min) and moderate intrinsic clearance (34.18 mL min-1 kg-1) of OSM indicate that it resembles drugs with a moderate extraction ratio. The present LC-MS/MS technique is regarded as the primary analytical methodology for quantifying OSM in HLM matrices. The characterization of OSM metabolic stability and in silico ADME features are crucial for progressing the discovery of novel drugs with improved metabolic stability.