title: LC-MS/MS bioanalytical method development for AMG 900: resolution of an isobaric interference in rodent in vivo studies.
abstract: AMG 900 is an orally available small molecule that is a highly potent and selective pan-aurora kinase inhibitor currently in development for the treatment of advanced human cancers. A co-eluting, isobaric interference was discovered in preliminary LC-MS/MS analyses of rodent in vivo pharmacokinetic samples during preclinical evaluation of AMG 900. The interference was identified as a major circulating N-oxide metabolite which partially converted to an [M+H-O](+) ion under the conditions of atmospheric pressure chemical ionization. A selective liquid chromatography-tandem mass spectrometry method for the simultaneous quantification of AMG 900 and its N-oxide metabolite in plasma was developed and successfully applied for the bioanalysis of discovery stage preclinical rodent pharmacokinetic studies.
authors.affiliation: Department of Pharmacokinetics and Drug Metabolism, Amgen, 360 Binney Street, Cambridge, MA 02142, United States.
authors.forename: Xuhai
authors.initials: X
authors.lastname: Be
authors.forename: Earl S
authors.initials: ES
authors.lastname: Moore
authors.forename: Zhiyang
authors.initials: Z
authors.lastname: Zhao
authors.forename: Mary C
authors.initials: MC
authors.lastname: Wells
mesh_terms: D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods; D008297:Male; D051379:Mice; D010793:Phthalazines / Q000032:analysis* / Q000097:blood / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053719:Tandem Mass Spectrometry / Q000379:methods*
chemical_list: C555658:N-(4-((3-(2-amino-4-pyrimidinyl)-2-pyridinyl)oxy)phenyl)-4-(4-methyl-2-thienyl)-1-phthalazinamine; D010793:Phthalazines