Chromatographic bioanalytical assays for targeted covalent kinase inhibitors and their metabolites

J Chromatogr B Analyt Technol Biomed Life Sci. 2021 Jan 1:1162:122466. doi: 10.1016/j.jchromb.2020.122466. Epub 2020 Nov 30.

Abstract

Deriving from targeted kinase inhibitors (TKIs), targeted covalent kinase inhibitors (TCKIs) are a new class of TKIs that are covalently bound to their target residue of kinase receptors. Currently, there are many new TCKIs under clinical development besides afatinib, ibrutinib, osimertinib, neratinib, acalabrutinib, dacomitinib, and zanubrutinib that are already approved by the FDA. Subsequently, there is an increasing demand for bioanalytical methods to qualitatively and quantitively investigate those compounds, leading to a number of papers reporting the development, validation, and use of bioanalytical methods for TCKIs. Most publications describe the technological set up of analytical methods that allow quantification of TCKIs in various biomatrices such as plasma, cerebrospinal fluid, urine, tissue, and liver microsomes. In addition, the identification of metabolites and biotransformation pathways of new TCKIs has gained more interest in recent years. We provide an overview of bioanalytical methods of this new class of TCKIs. The included issues are sample pretreatment, chromatographic separation, detection, and method validation. In the scope of bioanalysis of TCKIs, protein precipitation is mostly applied to treat the biological matrices sample. Liquid chromatographic in reversed-phase mode (RPLC) and mass detection with triple quadrupole (QqQ) are the most often utilized separation and quantitative detection modes, respectively. There may be a possibility of increased use of the high-resolution mass spectrometry (HRMS) for qualitative investigation purposes in the future. We also found that US FDA and EMA guidelines are the most common guidelines employed as validation framework for the bioanalytical methods of TCKIs.

Keywords: Biomatrices; Chromatography; Covalent targeted kinase inhibitors; Mass spectrometry; Metabolites.

Publication types

  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents* / analysis
  • Antineoplastic Agents* / metabolism
  • Chromatography, Liquid*
  • Humans
  • Mice
  • Protein Kinase Inhibitors* / analysis
  • Protein Kinase Inhibitors* / metabolism
  • Rats
  • Reproducibility of Results
  • Tandem Mass Spectrometry*

Substances

  • Antineoplastic Agents
  • Protein Kinase Inhibitors