RT Journal Article
SR Electronic
T1 Apalutamide Absorption, Metabolism, and Excretion in Healthy Men, and Enzyme Reaction in Human Hepatocytes
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 453
OP 464
DO 10.1124/dmd.118.084517
VO 47
IS 5
A1 Ronald de Vries
A1 Frank Jacobs
A1 Geert Mannens
A1 Jan Snoeys
A1 Filip Cuyckens
A1 Caly Chien
A1 Peter Ward
YR 2019
UL http://dmd.aspetjournals.org/content/47/5/453.abstract
AB 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 of apalutamide orally plus a 15-minute intravenous infusion of 100 µg of apalutamide containing 9.25 kBq (250 nCi) of 14C-apalutamide (2 hours postdose) for absolute bioavailability assessment or plus one 400-µg capsule containing 37 kBq (1000 nCi) of 14C-apalutamide for AME assessment. Content of 14C and metabolite profiling for whole blood, plasma, urine, feces, and expired air samples were analyzed using accelerator mass spectrometry. Apalutamide absolute oral bioavailability was ≈100%. After oral administration, apalutamide, its N-desmethyl metabolite (M3), and an inactive carboxylic acid metabolite (M4) accounted for most 14C in plasma (45%, 44%, and 3%, respectively). Apalutamide elimination was slow, with a mean plasma half-life of 151–178 hours. The mean cumulative recovery of total 14C over 70 days postdose was 64.6% in urine and 24.3% in feces. The 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.