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

Abstract

1. 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.

2. 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).

3. 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.

4. 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.

Keywords:

• SH-1028
• LC-MS/MS
• human plasma
• EGFR-TKIs
• pharmacokinetics

Ethical approval

No animal related experiments involved in our research.

Disclosure statement

The authors report no declarations of interest.

Data availability statement

The data are available from the corresponding author upon reasonable request.

Additional information

Funding

This study was funded by Sanhome Pharmaceutical Co., Ltd. (Nanjing, China).