title: A simple and rapid UHPLC-MS/MS method for the quantitation of the dual aurora kinase A/B inhibitor SCH-1473759 in murine plasma.
abstract: The Aurora kinase family facilitates cell division through various processes and is overexpressed in a wide variety of human cancers, leading to aneuploidy. For that reason, these enzymes are currently targets of a rising class of anticancer drugs, with some molecules already in therapeutic use. In this study, a new UHPLC-MS/MS method was developed and validated to quantitate a new pan Aurora kinase inhibitor still in preclinical development, SCH-1473759. This bioanalytical method employed a liquid-liquid extraction from plasma using ethyl acetate before evaporation. Calibration range encompassed 0.5-2500ng/mL. The inter- and intra-day accuracy and precision were assessed over five quality control levels; all within limits required by the FDA guidelines. Assay applicability was demonstrated in a first-in-animals study with oral administration, where the maximum plasma concentration (34ng/mL) occurred at 1h, the half-life (1h) was consistent with a previous IV study, and oral bioavailability was poor (F=0.002).
authors: Clinical Pharmacology Program, Office of the Clinical Director, National Cancer Institute, Bethesda, MD, USA; CAPES Foundation, Ministry of Education of Brazil, Brasília, DF, Brazil.
authors: Marco A
authors: MA
authors: Ferraz Nogueira Filho
authors: Clinical Pharmacology Program, Office of the Clinical Director, National Cancer Institute, Bethesda, MD, USA.
authors: Cody J
authors: CJ
authors: Peer
authors: Clinical Pharmacology Program, Office of the Clinical Director, National Cancer Institute, Bethesda, MD, USA.
authors: Jeffers
authors: J
authors: Nguyen
authors: Molecular Oncology Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors: Amy
authors: A
authors: McCalla
authors: Molecular Oncology Section, Pediatric Oncology Branch, National Cancer Institute, Bethesda, MD, USA.
authors: Lee
authors: L
authors: Helman
authors: Clinical Pharmacology Program, Office of the Clinical Director, National Cancer Institute, Bethesda, MD, USA. Electronic address: figgw@helix.nih.gov.
authors: William D
authors: WD
authors: Figg
mesh_terms: D000284:Administration, Oral; D000818:Animals; D064096:Aurora Kinase A / Q000037:antagonists & inhibitors*; D064107:Aurora Kinase B / Q000037:antagonists & inhibitors*; D001682:Biological Availability; D002851:Chromatography, High Pressure Liquid; D004355:Drug Stability; D006207:Half-Life; D007093:Imidazoles / Q000097:blood*; D016014:Linear Models; D059625:Liquid-Liquid Extraction; D051379:Mice; D010949:Plasma / Q000737:chemistry; D011719:Pyrazines / Q000097:blood*; D011786:Quality Control; D015203:Reproducibility of Results; D053719:Tandem Mass Spectrometry
chemical_list: D007093:Imidazoles; D011719:Pyrazines; C568063:SCH 1473759; D064096:Aurora Kinase A; D064107:Aurora Kinase B
keywords: Aurora kinases; Mice; UHPLC–MS/MS pharmacokinetics