Pharmacology
Pharmacodynamics
Darolutamide is a second- or third-generation nonsteroidal antiandrogen (NSAA). It acts as a selective competitive silent antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). Its affinity (Ki) for the AR is 11 nM and its functional inhibition (IC50) of the AR is 26 nM. The major metabolite of darolutamide, ketodarolutamide, has similar antiandrogenic activity relative to darolutamide (Ki = 8 nM; IC50 = 38 nM). In addition to its actions as an AR antagonist, darolutamide has been found to act as a silent antagonist of the progesterone receptor (PR), with approximately 1% of the potency of its AR antagonism.A dosage of darolutamide of 1,200 mg/day has been found to result in a mean decrease in prostate specific antigen (PSA) levels of more than 90% in men with prostate cancer. The addition of darolutamide to castration has been found to decrease PSA levels by more than 50% in about 50% of men at 200 mg/day, 69% of men at 400 mg/day, 83% of men at 1,200 mg/day, and 86% of men at 1,400 mg/day.Darolutamide shows some advantages in comparison to enzalutamide and apalutamide, two other second-generation NSAAs. It appears to negligibly cross the blood–brain barrier, and hence has reduced risk of seizures and other central side effects from off-target GABAA receptor inhibition. In accordance with its diminished central penetration, darolutamide does not appear to increase testosterone levels.
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.