Metabolism and Disposition of [¹⁴C]Brivanib Alaninate after Oral Administration to Rats, Monkeys, and Humans

Abstract

]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.

Identification of the Oxidative and Conjugative Enzymes Involved in the Biotransformation of Brivanib

“…LC/MS analysis indicated that brivanib was metabolized primarily to a hydroxy metabolite with a protonated molecular ion at m/z 387. This metabolite had the same HPLC retention time, as well as MS and MS/MS fragmentation patterns, as M7 that was characterized in a previous study (Gong et al, 2011). In addition, a carboxylic acid derivative (M26) and a ketone metabolite (M31), formed at much lower levels than M7, were also observed in the incubation mixture.…”

“…Similar to HLM-mediated metabolism, the prodrug was not observed after incubation due to rapid hydrolysis. Metabolism of brivanib in cytosol in the presence of PAPS yielded a sulfate conjugate with HPLC retention time, as well as MS and MS/MS fragmentation patterns identical to M25, a direct sulfate conjugate of brivanib characterized previously (Gong et al, 2011).…”

“…In addition, after an oral dose of brivanib alaninate to rats, monkeys, and humans, the exposure to the prodrug was minimal to none, suggesting rapid presystemic hydrolysis. Brivanib was the prominent circulating species in plasma and was extensively metabolized before excretion (Gong et al, 2011). The primary biotransformation pathways of brivanib in humans were methyl oxidation and direct sulfation (Gong et al, 2011).…”

“…Brivanib was the prominent circulating species in plasma and was extensively metabolized before excretion (Gong et al, 2011). The primary biotransformation pathways of brivanib in humans were methyl oxidation and direct sulfation (Gong et al, 2011).…”

“…The objective of this study was to characterize the primary human P450 and SULT enzymes involved in the metabolism of brivanib, and the human CEs involved in the hydrolysis of brivanib alaninate. In addition, further metabolism studies of the primary oxidative metabolite (M7) were conducted in liver subcellular fractions to confirm the link between M7 and the secondary metabolites of brivanib that were observed in vivo (Gong et al, 2011 (Marathe et al, 2009). In incubations with recombinant enzymes and with HLM in the presence of selective P450 inhibitors and monoclonal P450 antibody, brivanib was used as substrate.…”