Quantitation of the DNA-dependent protein kinase inhibitor peposertib (M3814) and metabolite in human plasma by LC-MS/MS.
DNA‐PK
assay
chromatography
peposertib
tandem mass spectrometry
validation
Journal
Biomedical chromatography : BMC
ISSN: 1099-0801
Titre abrégé: Biomed Chromatogr
Pays: England
ID NLM: 8610241
Informations de publication
Date de publication:
08 Oct 2024
08 Oct 2024
Historique:
revised:
18
09
2024
received:
24
06
2024
accepted:
27
09
2024
medline:
9
10
2024
pubmed:
9
10
2024
entrez:
8
10
2024
Statut:
aheadofprint
Résumé
The DNA-dependent protein kinase (DNA-PK) is an abundant nuclear protein that mediates DNA double-strand break repair by nonhomologous end joining (NHEJ). As such, DNA-PK is critical for V(D)J recombination in lymphocytes and for survival in cells exposed to ionizing radiation and clastogens. Peposertib (M3814) is a small molecule DNA-PK inhibitor currently in preclinical and clinical development for cancer treatment. We have developed a high-performance liquid chromatography-mass spectrometry method for quantitating peposertib and its metabolite in 0.1 mL human plasma. After MTBE liquid-liquid extraction, chromatographic separation was achieved with a Phenomenex Synergi polar reverse phase (4 μm, 2 × 50 mm) column and a gradient of 0.1% formic acid in acetonitrile and water over an 8 min run time. Mass spectrometric detection was performed on an ABI SCIEX 4000 with electrospray, positive-mode ionization. The assay was linear from 10 to 3000 ng/mL for peposertib and 1-300 ng/mL for the metabolite and proved to be both accurate (97.3%-103.7%) and precise (<8.9%CV) fulfilling criteria from the Food and Drug Administration (FDA) guidance on bioanalytical method validation. This liquid chromatography-tandem mass spectroscopy (LC-MS/MS) assay will support several ongoing clinical studies by defining peposertib pharmacokinetics.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e6024Subventions
Organisme : NCI NIH HHS
ID : R50 CA211241
Pays : United States
Organisme : NCI NIH HHS
ID : R01CA266172
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA186690
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA247643
Pays : United States
Organisme : UPMC Hillman Cancer Center's Cancer Pharmacokinetics and Pharmacodynamics Facility
ID : P30 CA47904
Organisme : Merck KGaA
ID : 10.13039/100009945
Informations de copyright
© 2024 The Author(s). Biomedical Chromatography published by John Wiley & Sons Ltd.
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