1. Academic Validation
  2. Development and validation of pharmacokinetics assays for a novel HER2-targeting antibody-drug conjugate (SHR-A1201): Application to its dose-escalation pharmacokinetic study

Development and validation of pharmacokinetics assays for a novel HER2-targeting antibody-drug conjugate (SHR-A1201): Application to its dose-escalation pharmacokinetic study

  • J Pharm Biomed Anal. 2024 Mar 15:240:115964. doi: 10.1016/j.jpba.2024.115964.
Xianjing Li 1 Yiya Wang 2 Wenhui Hu 3 Qinxin Song 4 Li Ding 5
Affiliations

Affiliations

  • 1 Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
  • 2 Nanjing Clinical Tech Laboratories Inc., 18 Zhilan Road, Jiangning District, Nanjing 211100, China.
  • 3 Nanjing Jiening Pharmaceutical Technology, 18 Zhilan Road, Jiangning District, Nanjing 211100, China.
  • 4 Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: songqinxin@cpu.edu.cn.
  • 5 Key Laboratory of Drug Quality Control and Pharmacovigilance, Ministry of Education, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Nanjing Clinical Tech Laboratories Inc., 18 Zhilan Road, Jiangning District, Nanjing 211100, China; Nanjing Jiening Pharmaceutical Technology, 18 Zhilan Road, Jiangning District, Nanjing 211100, China; Department of Pharmaceutical Analysis, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: dingli@cpu.edu.cn.
Abstract

Approximately 25% of breast Cancer patients with HER2 overexpression tend to have a high risk of disease progression and death. Various HER2-targeting therapies have been approved for treatment. Recently, a novel antibody-drug conjugate, SHR-A1201, is being researched and developed. For the pharmacokinetic study of SHR-A1201, suitable bioanalytical methods are needed for quantifying unconjugated cytotoxin, cytotoxin-conjugated Antibodies and total Antibodies. In this research, bioanalytical methods involving a highly sensitive LC-MS/MS assay for unconjugated cytotoxic payload DM1 in human plasma, ELISA strategies for DM1-conjugated trastuzumab and total trastuzumab in human serum were developed, validated and successfully applied to a phase I dose-escalation pharmacokinetic study of SHR-A1201. The pharmacokinetic properties and exposure-to-dose proportionality was evaluated for SHR-A1201. According to the bioanalytical method validation guidance, the bioanalytical methods were fully validated and the validation results met the acceptance criteria. The nonspecific binding of DM1 and dimer was avoided for the LC-MS/MS assay. In the dose-escalation pharmacokinetic study of SHR-A1201, a potential dose-proportional pharmacokinetics was observed over the dose from 1.2 mg/kg to 4.8 mg/kg. The validated bioanalytical strategies are robust and reproducible and these bioanalytical methods will contribute to better understanding of the pharmacokinetic properties of SHR-A1201.

Keywords

Antibody-drug conjugate; Bioanalysis; Exposure-to-dose proportionality; Pharmacokinetics; SHR-A1201.

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