Apalutamide Absorption, Metabolism, and Excretion in Healthy Men, and Enzyme Reaction in Human Hepatocytes

• Published in: Drug metabolism and disposition Vol. 47; no. 5; pp. 453 - 464
• Main Authors: de Vries, Ronald, Jacobs, Frank, Mannens, Geert, Snoeys, Jan, Cuyckens, Filip, Chien, Caly, Ward, Peter
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics, Inc 01-05-2019
• Subjects: Absorption; Aged; Aged, 80 and over; Androgen receptors; Bioavailability; Biological Availability; Body Fluids - metabolism; Carbon 14; Carbon Radioisotopes - metabolism; Carboxylic acids; Cytochrome P-450 CYP2C8 - metabolism; Cytochrome P-450 CYP3A - metabolism; Excretion; Expired air; Feces; Feces - chemistry; Half-Life; Hepatocytes; Hepatocytes - metabolism; Humans; Infusions, Intravenous - methods; Intravenous administration; Intravenous infusion; Male; Mass spectrometry; Mass spectroscopy; Metabolic Clearance Rate - physiology; Metabolism; Metabolites; Middle Aged; Oral administration; Thiohydantoins - metabolism; Urine
• ISSN: 0090-9556; 1521-009X
• DOI: 10.1124/dmd.118.084517

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
g of apalutamide containing 9.25 kBq (250 nCi) of
C-apalutamide (2 hours postdose) for absolute bioavailability assessment or plus one 400-
g capsule containing 37 kBq (1000 nCi) of
C-apalutamide for AME assessment. Content of
C 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
-desmethyl metabolite (M3), and an inactive carboxylic acid metabolite (M4) accounted for most
C 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
C 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.