TY - JOUR T1 - Apalutamide Absorption, Metabolism, and Excretion in Healthy Men, and Enzyme Reaction in Human Hepatocytes JF - Drug Metabolism and Disposition JO - Drug Metab Dispos DO - 10.1124/dmd.118.084517 SP - dmd.118.084517 AU - Ronald de Vries AU - Frank Jacobs AU - Geert Mannens AU - Jan Snoeys AU - Filip Cuyckens AU - Caly Chien AU - Peter Ward Y1 - 2019/01/01 UR - http://dmd.aspetjournals.org/content/early/2019/02/20/dmd.118.084517.abstract N2 - In this phase 1 study, the absolute bioavailability and absorption, metabolism, and excretion (AME) of apalutamide, a competitive inhibitor of the androgen receptor, were evaluated in 12 healthy men. Subjects received 240 mg apalutamide orally plus a 15-minute intravenous infusion of 100 µg apalutamide containing 9.25 kBq (250 nCi) of 14C-apalutamide (2 hours post dose) for absolute bioavailability assessment or plus one 400 µg capsule containing 37 kBq (1000 nCi) of 14C-apalutamide for AME assessment. Total radioactivity and metabolite profiling for whole blood, plasma, urine, feces, and expired air samples were analyzed using accelerator mass spectrometry or liquid scintillation counting. Apalutamide absolute oral bioavailability was ≈100%. Following oral administration, apalutamide, its N-desmethyl metabolite (M3), and an inactive carboxylic acid metabolite (M4) accounted for most 14C-radioactivity in plasma (45%, 44%, and 3%, respectively). Apalutamide elimination was slow, with mean plasma half-life of 151-178 hours. Mean cumulative recovery of total 14C-radioactivity over 70 days post dose was 64.6% in urine and 24.3% in feces. Urinary excretion of apalutamide, M3, and M4, was 1.2%, 2.7%, and 31.1% of dose, respectively. Fecal excretion of apalutamide, M3, and M4 was 1.5%, 2.0%, and 2.4% of dose, respectively. Seventeen apalutamide metabolites and six main metabolic clearance pathways were identified. In vitro studies confirmed CYP2C8 and CYP3A4 roles in apalutamide metabolism. ER -