Routes of
administration Oral PubChem CID 67171867 UNII X05U0N2RCO | CAS Number 1297538-32-9 ChemSpider 38772320 Molar mass 398.8462 g/mol | |
Biological half-life Parent: 15.8 hours
Metabolite: 10.0 hours | ||
Darolutamide (INN) (developmental code names ODM-201, BAY-1841788) is a non-steroidal antiandrogen (NSAA) – specifically, a selective high affinity silent antagonist of the androgen receptor (AR) – that is under development by Orion and Bayer HealthCare[1] for the treatment of advanced, castration-resistant prostate cancer (CRPC).
Contents
Pharmacology
Relative to enzalutamide (MDV3100 or Xtandi) and apalutamide (ARN-509), two other recent NSAAs, darolutamide shows some advantages. Darolutamide appears to negligibly cross the blood-brain-barrier. This is beneficial due to the reduced risk of seizures and other central side effects from off-target GABAA receptor inhibition that tends to occur in NSAAs that are structurally similar to enzalutamide. Moreover, in accordance with its lack of central penetration, darolutamide does not seem to increase testosterone levels in mice or humans, unlike other NSAAs. Another advantage is that darolutamide has been found to block the activity of all tested/well-known mutant ARs in prostate cancer, including the recently identified clinically-relevant F876L mutation that produces resistance to enzalutamide and apalutamide. Finally, darolutamide shows higher affinity and inhibitory efficacy at the AR (Ki = 11 nM relative to 86 nM for enzalutamide and 93 nM for apalutamide; IC50 = 26 nM relative to 219 nM for enzalutamide and 200 nM for apalutamide) and greater potency/efficaciousness in non-clinical models of prostate cancer.
ORM-15341 is the main active metabolite of darolutamide. It is a full antagonist of the AR similarly, with an affinity (Ki) of 8 nM and an IC50 of 38 nM.
Unlike enzalutamide and apalutamide, darolutamide shows no inhibition or induction of cytochrome P450 enzymes at therapeutic concentrations.
Pharmacokinetics
The mean terminal half-lives of darolutamide and its active metabolite ORM-15341 at steady-state are 15.8 hours and 10.0 hours, respectively. The half-lives are independent of dosage with 200–1800 mg/day dosages of darolutamide. The half-life of darolutamide is far shorter than that of enzalutamide (1.6 hours and 18.3 hours in mice, respectively), necessitating higher dosages and more frequent administration in the case of darolutamide.
Chemistry
Darolutamide is structurally distinct from any other known or established antiandrogens, including enzalutamide and apalutamide.
Clinical trials
Darolutamide has been studied in phase I and phase II clinical trials and has thus far been found to be effective and well-tolerated, with the most commonly reported side effects including fatigue, nausea, and diarrhea. No seizures have been observed. As of June 2016, darolutamide is in phase III trials for CRPC.