Following a single 600-mg dose of darolutamide, peak levels of darolutamide occur after approximately 4 hours. Steady-state levels of darolutamide occur after 2 to 5 days of continuous administration with food, during which time an approximate 2-fold accumulation in darolutamide levels occurs. At steady state with 600 mg/day darolutamide, mean levels of darolutamide are 4.79 μg/mL and area-under-the-curve levels of darolutamide over time 0 to 12 hours (AUC0–12) are 52.82 h•μg/mL. Total exposure to ketodarolutamide is approximately 1.7-fold that of darolutamide. Distribution
The volume of distribution of darolutamide with intravenous administration is 119 L. The plasma protein binding of darolutamide is 92%, with 8% circulating freely, and of ketodarolutamide is 99.8%, with 0.2% circulating unbound. As such, free levels of darolutamide in the circulation are about 40-fold higher than those of ketodarolutamide. Both darolutamide and ketodarolutamide are bound mainly to albumin. Darolutamide and ketodarolutamide appear to negligibly cross the blood–brain barrier both in mice and humans. Darolutamide is a known substrate of P-glycoprotein and the breast cancer resistance protein (BCRP). P-Glycoprotein is known to play a major role in excluding drugs from the brain due to efflux back across the blood–brain barrier. Metabolism
Darolutamide is primarily metabolized into ketodarolutamide via dehydrogenation by CYP3A4 in the liver. The medication is also conjugated via glucuronidation by UGT1A9 and UGT1A1. The elimination half-life of darolutamide and ketodarolutamide has been reported to be approximately 20 hours.
A clinical study found that the elimination half-lives of darolutamide and ketodarolutamide at steady-state were 15.8 hours and 10.0 hours, respectively, with these half-lives being independent of dosage across a dose range of darolutamide of 200 to 1,800 mg/day. The elimination half-life of darolutamide is far shorter than that of enzalutamide (e.g., 1.6 hours vs. 18.3 hours in mice). The clearance of darolutamide following intravenous administration is 116 mL/min. Excretion
After a single oral dose of darolutamide, more than 95% of the dose is excreted in urine and feces within one week following administration. A total of 63.4% darolutamide-related material is recovered in urine (about 7% as unchanged darolutamide) and a total of 32.4% darolutamide-related material (about 30% as unchanged darolutamide) is recovered in feces. Variability
No clinically significant differences in the pharmacokinetics of darolutamide have been observed in men with nmCRPC on the basis of age (48 to 95 years), race (white, Asian, black), mild-to-moderate renal impairment, or mild hepatic impairment. In non-nmCRPC individuals with severe renal impairment not on dialysis, exposure to darolutamide was increased by about 2.5-fold relative to healthy people. In non-nmCRPC individuals with moderate hepatic impairment, darolutamide exposure was increased by about 1.9-fold compared to healthy controls. The pharmacokinetics of darolutamide have not been assessed in end-stage kidney disease or severe hepatic impairment. Chemistry
Darolutamide is a nonsteroidal compound and is structurally distinct from other marketed NSAAs, including enzalutamide and apalutamide. History
Darolutamide was developed by Orion Corporation and Bayer HealthCare.