title: Metabolism and disposition of [14C]brivanib alaninate after oral administration to rats, monkeys, and humans.
abstract: Brivanib [(R)-1-(4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[1,2,4]triazin-6-yloxy)propan-2-ol, BMS-540215] is a potent and selective dual inhibitor of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways. Its alanine prodrug, brivanib alaninate [(1R,2S)-2-aminopropionic acid 2-[4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-5-methylpyrrolo[2,1-f][1,2,4]triazin-6-yloxy]-1-methylethyl ester, BMS-582664], is currently under development as an oral agent for the treatment of cancer. This study describes the in vivo biotransformation of brivanib after a single oral dose of [(14)C]brivanib alaninate to intact rats, bile duct-cannulated (BDC) rats, intact monkeys, BDC monkeys, and humans. Fecal excretion was the primary route of elimination of drug-derived radioactivity in animals and humans. In BDC rats and monkeys, the majority of radioactivity was excreted in bile. Brivanib alaninate was rapidly and completely converted via hydrolysis to brivanib in vivo. The area under the curve from zero to infinity of brivanib accounted for 14.2 to 54.3% of circulating radioactivity in plasma in animals and humans, suggesting that metabolites contributed significantly to the total drug-related radioactivity. In plasma from animals and humans, brivanib was a prominent circulating component. All the metabolites that humans were exposed to were also present in toxicological species. On the basis of metabolite exposure and activity against VEGF and FGF receptors of the prominent human circulating metabolites, only brivanib is expected to contribute to the pharmacological effects in humans. Unchanged brivanib was not detected in urine or bile samples, suggesting that metabolic clearance was the primary route of elimination. The primary metabolic pathways were oxidative and conjugative metabolism of brivanib.
authors.affiliation: Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, P.O. Box 4000, Princeton, NJ 08543, USA. jiachang.gong@bms.com
authors.forename: Jiachang
authors.initials: J
authors.lastname: Gong
authors.forename: Jinping
authors.initials: J
authors.lastname: Gan
authors.forename: Janet
authors.initials: J
authors.lastname: Caceres-Cortes
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Christopher
authors.forename: Vinod
authors.initials: V
authors.lastname: Arora
authors.forename: Eric
authors.initials: E
authors.lastname: Masson
authors.forename: Daphne
authors.initials: D
authors.lastname: Williams
authors.forename: Janice
authors.initials: J
authors.lastname: Pursley
authors.forename: Alban
authors.initials: A
authors.lastname: Allentoff
authors.forename: Michael
authors.initials: M
authors.lastname: Lago
authors.forename: Scott B
authors.initials: SB
authors.lastname: Tran
authors.forename: Ramaswamy A
authors.initials: RA
authors.lastname: Iyer
mesh_terms: D000284:Administration, Oral; D000409:Alanine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000378:metabolism / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D001646:Bile / Q000378:metabolism; D001711:Biotransformation; D005243:Feces; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D009369:Neoplasms / Q000188:drug therapy; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D014227:Triazines / Q000008:administration & dosage / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D014227:Triazines; C509922:brivanib; D040301:Vascular Endothelial Growth Factor Receptor-2; D000409:Alanine