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

Sufeng Zhou, Bijun Sha,Lu Wang,Yuqing Zhao,Zhiqiang Wang,Xian Zhang,Luwei Han,Feng Shao,Xijing Chen

Xenobiotica; the fate of foreign compounds in biological systems（2023）SCI 4区

Nanjing Med Univ

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Abstract

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 C-max of SH-1028, Imp2, and Imp3 was 11.2, 50.2, and 7.99 ng/mL, respectively. The mean AUC(0-24 h) 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 (R-AUC) 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.

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Key words

SH-1028,LC-MS,MS,human plasma,EGFR-TKIs,pharmacokinetics

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