Development and validation of an LC-MS/MS method for simultaneous determination of SH-1028, an irreversible third-generation EGFR TKI, and two of its metabolites in human plasma: application in clinical pharmacokinetics.

SH-1028 is a novel, potent, and highly selective epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) developed for the treatment of T790M Mutation-positive non-small cell lung cancer (NSCLC). The objective was to develop an LC-MS/MS method for the simultaneous determination of SH-1028 and its metabolites, Imp2 and Imp3, in human plasma.The plasma samples were extracted through protein precipitation with acetonitrile on wet ice conditions. A rapid, sensitive, and specific method was developed and successfully applied to evaluate the pharmacokinetic (PK) properties of SH-1028 in patients with advanced NSCLC following single and multiple doses of SH-1028 (60 mg).After single-dose administration, the of SH-1028, Imp2, and Imp3 was 11.2, 50.2, and 7.99 ng/mL, respectively. The mean AUC was 138, 602, and 76.7 h*ng/mL, respectively. And the terminal half-life time was 19.9, 14.4, and 26.1 h, respectively. After multiple-dose administration, SH-1028 exhibited a slight accumulation, with a mean accumulation ratio () of 2.00.The study assessed the PK properties of SH-1028 following single and multiple doses in patients with advanced NSCLC and would provide meaningful information for the further development of SH-1028.