title: Metabolic chiral inversion of brivanib and its relevance to safety and pharmacology.
abstract: Brivanib alaninate is an orally administered alanine prodrug of brivanib, a dual inhibitor of the vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) signaling pathways. It is currently in clinical trials for the treatment of hepatocellular carcinoma and colorectal cancer. Brivanib has a single asymmetric center derived from a secondary alcohol. The potential for chiral inversion was investigated in incubations with liver subcellular fractions and in animals and humans after oral doses of brivanib alaninate. Incubations of [¹⁴C]brivanib alaninate with liver microsomes and cytosols from rats, monkeys, and humans followed by chiral chromatography resulted in two radioactive peaks, corresponding to brivanib and its enantiomer. The percentage of the enantiomeric metabolite relative to brivanib in microsomal and cytosolic incubations of different species in the presence of NADPH ranged from 11.6 to 15.8 and 0.8 to 3.1%, respectively. The proposed mechanism of inversion involves the oxidation of brivanib to a ketone metabolite, which is subsequently reduced to brivanib and its enantiomer. After oral doses of brivanib alaninate to rats and monkeys, the enantiomeric metabolite was a prominent drug-related component in plasma, with the percentages of area under the curve (AUC) at 94.7 and 39.7%, respectively, relative to brivanib. In humans, the enantiomeric metabolite was a minor circulating component, with the AUC <3% of brivanib. Pharmacological studies indicated that brivanib and its enantiomer had similar potency toward the inhibition of VEGF receptor-2 and FGF receptor-1 kinases. Because of low plasma concentration in humans, the enantiomeric metabolite was not expected to contribute significantly to target-related pharmacology of brivanib. Moreover, adequate exposure in the toxicology species suggested no specific safety concerns with respect to exposure to the enantiomeric metabolite.
authors.affiliation: 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: Eric
authors.initials: E
authors.lastname: Masson
authors.forename: Shariq
authors.initials: S
authors.lastname: Syed
authors.forename: Yuan-Qing
authors.initials: YQ
authors.lastname: Xia
authors.forename: Daphne
authors.initials: D
authors.lastname: Williams
authors.forename: Janice
authors.initials: J
authors.lastname: Pursley
authors.forename: Mohammed
authors.initials: M
authors.lastname: Jemal
authors.forename: W Griff
authors.initials: WG
authors.lastname: Humphreys
authors.forename: Ramaswamy A
authors.initials: RA
authors.lastname: Iyer
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000409:Alanine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006801:Humans; D007659:Ketones / Q000378:metabolism; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D009249:NADP / Q000378:metabolism; D010084:Oxidation-Reduction; D051381:Rats; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000037:antagonists & inhibitors; D014227:Triazines / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors; D055815:Young Adult
chemical_list: D007659:Ketones; D014227:Triazines; D009249:NADP; C509922:brivanib; D051496:Receptor, Fibroblast Growth Factor, Type 1; D040301:Vascular Endothelial Growth Factor Receptor-2; D000409:Alanine