title: Preclinical pharmacokinetics and in vitro metabolism of BMS-690514, a potent inhibitor of EGFR and VEGFR2.
abstract: BMS-690514, a potent inhibitor of human epidermal growth factor receptor (HER) 1 (EGFR), 2, and 4, and vascular endothelial growth factor receptors (VEGFR) 1-3, is currently under investigation as an oral agent for the treatment of solid tumors. In vitro and in vivo studies were conducted to characterize the pharmacokinetics and metabolism. Through integration of in vitro and in vivo pharmacokinetic data and antitumor efficacy in nude mice, human pharmacokinetics and efficacious doses were projected for BMS-690514. The oral bioavailability of BMS-690514 was 78% in mice, approximately 100% in rats, 8% in monkeys, and 29% in dogs. The low oral bioavailability in monkeys could be attributed to high systemic clearance in that species, which was also consistent with predicted clearance using in vitro data from monkey liver microsomes. Permeability of BMS-690514 in Caco-2 cells was in the intermediate range with a moderate potential to be a P-gp substrate. Experiments using recombinant human CYP enzymes and human liver microsomes suggested that CYP2D6 and CYP3A4 are likely to play a key role in the metabolic clearance of BMS-690514; in addition, direct glucuronidation of BMS-690514 was also observed in human hepatocytes. BMS-690514 was able to cross the blood-brain barrier with a brain-to-plasma ratio of approximately 1. The preclinical ADME properties of BMS-690514 suggest good oral bioavailability in humans and metabolism by multiple pathways including oxidation and glucuronidation. Based on the efficacious AUC in nude mice and predicted human pharmacokinetics, the human efficacious QD dose is predicted to be in the range of 100-200 mg.
authors.affiliation: Department of Metabolism and Pharmacokinetics, Bristol-Myers Squibb Company, Princeton, New Jersey, USA. punit.marathe@bms.com
authors.forename: Punit
authors.initials: P
authors.lastname: Marathe
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Tang
authors.forename: Bogdan
authors.initials: B
authors.lastname: Sleczka
authors.forename: David
authors.initials: D
authors.lastname: Rodrigues
authors.forename: Ashvinikumar
authors.initials: A
authors.lastname: Gavai
authors.forename: Tai
authors.initials: T
authors.lastname: Wong
authors.forename: Lisa
authors.initials: L
authors.lastname: Christopher
authors.forename: Hongjian
authors.initials: H
authors.lastname: Zhang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000465:Algorithms; D000818:Animals; D001798:Blood Proteins / Q000737:chemistry; D001923:Brain Chemistry; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D002851:Chromatography, High Pressure Liquid; D003198:Computer Simulation; D004285:Dogs; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005079:Excipients; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D010880:Piperidines / Q000032:analysis / Q000493:pharmacokinetics*; D011485:Protein Binding; D011758:Pyrroles / Q000032:analysis / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D053719:Tandem Mass Spectrometry; D014227:Triazines / Q000032:analysis / Q000493:pharmacokinetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C552150:BMS-690514; D001798:Blood Proteins; D005079:Excipients; D010880:Piperidines; D011758:Pyrroles; D014227:Triazines; D066246:ErbB Receptors; D040301:Vascular Endothelial Growth Factor Receptor-2