A Clinical Degrader's Human ADME: Low Bioavailability, Fecal Clearance, One Dominant Metabolite
- A radiolabel mass-balance study of the androgen receptor degrader BMS-986365 in healthy men combined an oral dose with an IV microtracer, so absorption and gut extraction could be separated.
- Oral bioavailability was low, driven partly by gut-wall metabolism, and elimination was almost entirely fecal with little renal excretion.
- One N-dealkylation-derived metabolite dominated circulating drug-related material, far above the parent; the two diastereomers were dosed and tracked separately.
💡 Points Based on the abstract
That a single metabolite outweighs parent in plasma is the first thing I'd chase: does it keep AR-degrading activity, and was it covered in the tox species? Low bioavailability plus heavy gut-wall extraction also means food and CYP3A modulators could move exposure, so the DDI package matters more than for a typical oral small molecule. Degraders are rarely this well characterized in humans, so this is a useful benchmark.
📄 Paper · Drug Metabolism and Disposition ↗ Absorption, distribution, metabolism, and excretion of the BMS-986365 ligand-directed degrader diastereomers, R,R-[14C]BMS-986409 and R,S-[14C]BMS-986410, following oral administration in combination with an intravenous microtracer in healthy male participants