Quantitation of the ataxia-telangiectasia-mutated and Rad3-related inhibitor elimusertib (BAY-1895344) in human plasma using LC-MS/MS.
Brian F KieselRobert A PariseAnuradha KrishnamurthySteven GoreJan H BeumerPublished in: Biomedical chromatography : BMC (2022)
Ataxia-telangiectasia-mutated and Rad3-related (ATR) is master regulator of the DNA-damage response that, through multiple mechanisms, can promote cancer cell survival in response to replication stress from sources, including chemotherapy and radiation. Elimusertib (BAY-1895344) is an orally available small-molecule ATR inhibitor currently in preclinical and clinical development for cancer treatment. To support these studies and define elimusertib pharmacokinetics, we developed a HPLC-MS method for its quantitation. A 50-μL volume of plasma was subjected to acetonitrile protein precipitation and then chromatographic separation using a Phenomenex Polar-RP column (2 × 50 mm, 4 μm) and a gradient mobile phase consisting of 0.1% formic acid in acetonitrile and water during a 7-min run time. Mass spectrometric detection was achieved using a SCIEX 4000 triple-stage mass spectrometer with electrospray positive-mode ionization. With a stable isotopic internal standard, the assay was linear from 30 to 5000 ng/mL and proved to be both accurate (93.5-108.2%) and precise (<6.3% coefficient of variation) fulfilling criteria from the Food and Drug Administration guidance on bioanalytical method validation. This LC-MS/MS assay will support several ongoing clinical studies by defining elimusertib pharmacokinetics.
Keyphrases
- dna damage response
- mass spectrometry
- liquid chromatography
- ms ms
- dna repair
- simultaneous determination
- small molecule
- tandem mass spectrometry
- high resolution
- solid phase extraction
- high performance liquid chromatography
- gas chromatography
- liquid chromatography tandem mass spectrometry
- dna damage
- drug administration
- high throughput
- early onset
- protein protein
- papillary thyroid
- multiple sclerosis
- transcription factor
- oxidative stress
- stem cells
- loop mediated isothermal amplification
- heat stress
- case control
- human health
- radiation induced
- ionic liquid
- lymph node metastasis
- amino acid
- stress induced