The disposition of radioactivity following subcutaneous 14C-razuprotafib, a Tie2 activator, was explored in multiple species.The absorption and clearance of razuprotafib and total radioactivity in human plasma are rapid and pharmacokinetics support razuprotafib as primary circulating component. Radioactivity is distributed greater to human plasma than whole blood (B:P = 0.36).In pigmented rats, radioactivity distributes to whole-body tissues rapidly and, within 24 h, is localised to elimination pathway end organs and injection site.Overall recovery of radioactivity across species is >93%, with the majority recovered within 24-48 h, and >80% in faeces.The CYP2C8 enzyme contributes significantly to razuprotafib metabolism.A hydrolysis product of razuprotafib (m/z- 380) is the main component in rat plasma at 2 h (49% peak area radioactivity), while razuprotafib (m/z- 585) is the main component in plasma for dog (58%), monkey (99.3%), and human (100%).Razuprotafib is present in dog, monkey, and human faeces, with the greatest percentage of radioactivity as metabolites. The major metabolite (>25%) in monkey and human, m/z- 633, is an S-methylated oxidised derivative of razuprotafib and is localised in faeces.Overall disposition of 14C-razuprotafib in human is best modelled by monkey over lower order species.
Keywords: AKB-9778; CYP2C8; Razuprotafib; distribution; excretion; mass balance; metabolism; phosphatase.