Darolutamide

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Darolutamide
ODM-201.svg
Clinical data
Synonyms ODM-201; BAY-1841788
Routes of
administration
By mouth
Drug class Nonsteroidal antiandrogen
ATC code
  • None
Pharmacokinetic data
Metabolites ORM-15341[1]
Elimination half-life Parent: 15.8 hours[1]
Metabolite: 10.0 hours[1]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
Chemical and physical data
Formula C19H19ClN6O2
Molar mass 398.85 g·mol−1
3D model (JSmol)
  (verify)

Darolutamide (developmental code names ODM-201, BAY-1841788) is a nonsteroidal antiandrogen (NSAA) – specifically, a selective antagonist of the androgen receptor (AR) – which is under development by Orion and Bayer HealthCare for the treatment of advanced, castration-resistant prostate cancer (CRPC).[2][3][4] As of April 2018, it is in phase III clinical trials for this indication,[2] it is taken by mouth.[2]

Medical uses[edit]

Darolutamide is intended for the treatment of castration-resistant prostate cancer.[3][4]

Pharmacology[edit]

Pharmacodynamics[edit]

Relative to enzalutamide (MDV3100 or Xtandi) and apalutamide (ARN-509 or Erleada), two other recent NSAAs, darolutamide shows some advantages.[4] Darolutamide appears to negligibly cross the blood–brain barrier,[4] 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.[4] Moreover, in accordance with its lack of central penetration, darolutamide does not seem to increase testosterone levels in mice or humans, unlike other NSAAs.[4] 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.[4] 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.[4]

ORM-15341 is the main active metabolite of darolutamide.[4] It is a full antagonist of the AR similarly, with an affinity (Ki) of 8 nM and an IC50 of 38 nM.[4]

Unlike enzalutamide and apalutamide, darolutamide shows no inhibition or induction of cytochrome P450 enzymes at therapeutic concentrations.[5]

Pharmacokinetics[edit]

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.[1] The half-lives are independent of dosage with 200–1800 mg/day dosages of darolutamide.[1] 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.[6]

Chemistry[edit]

Darolutamide is structurally distinct from any other known or established antiandrogens, including enzalutamide and apalutamide.[6]

History[edit]

Clinical trials[edit]

Darolutamide has been studied in phase I and phase II clinical trials and has thus far been found to be effective and well-tolerated,[7] with the most commonly reported side effects including fatigue, nausea, and diarrhea.[8][9] No seizures have been observed,[9][10] as of April 2018, darolutamide is in phase III trials for CRPC.[2][4]

Society and culture[edit]

Generic names[edit]

Darolutamide is the generic name of the drug and its INN and USAN.[11] It is also known by its developmental code names ODM-201 and BAY-1841788.[2]

See also[edit]

References[edit]

  1. ^ a b c d e Fizazi, Karim; Massard, Christophe; Bono, Petri; Jones, Robert; Kataja, Vesa; James, Nicholas; Garcia, Jorge A; Protheroe, Andrew; Tammela, Teuvo L; Elliott, Tony; Mattila, Leena; Aspegren, John; Vuorela, Annamari; Langmuir, Peter; Mustonen, Mika (2014). "Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial". The Lancet Oncology. 15 (9): 975–985. doi:10.1016/S1470-2045(14)70240-2. ISSN 1470-2045. PMID 24974051. 
  2. ^ a b c d e http://adisinsight.springer.com/drugs/800033671
  3. ^ a b Fizazi K, Albiges L, Loriot Y, Massard C (2015). "ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer". Expert Rev Anticancer Ther. 15 (9): 1007–17. doi:10.1586/14737140.2015.1081566. PMC 4673554Freely accessible. PMID 26313416. 
  4. ^ a b c d e f g h i j k Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (2015). "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Sci Rep. 5: 12007. doi:10.1038/srep12007. PMC 4490394Freely accessible. PMID 26137992. 
  5. ^ http://meetinglibrary.asco.org/content/114000117-144
  6. ^ a b Moilanen, Anu-Maarit; Riikonen, Reetta; Oksala, Riikka; Ravanti, Laura; Aho, Eija; Wohlfahrt, Gerd; Nykänen, Pirjo S.; Törmäkangas, Olli P.; Palvimo, Jorma J.; Kallio, Pekka J. (2015). "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Scientific Reports. 5: 12007. doi:10.1038/srep12007. ISSN 2045-2322. PMC 4490394Freely accessible. PMID 26137992. 
  7. ^ "ODM-201 is safe and active in metastatic castration-resistant prostate cancer". Cancer Discov. 4 (9): OF10. 2014. doi:10.1158/2159-8290.CD-RW2014-150. PMID 25185192. 
  8. ^ Pinto Á (2014). "Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer". Cancer Biol. Ther. 15 (2): 149–55. doi:10.4161/cbt.26724. PMC 3928129Freely accessible. PMID 24100689. 
  9. ^ a b Fizazi K, Massard C, Bono P, Jones R, Kataja V, James N, Garcia JA, Protheroe A, Tammela TL, Elliott T, Mattila L, Aspegren J, Vuorela A, Langmuir P, Mustonen M (2014). "Activity and safety of ODM-201 in patients with progressive metastatic castration-resistant prostate cancer (ARADES): an open-label phase 1 dose-escalation and randomised phase 2 dose expansion trial". Lancet Oncol. 15 (9): 975–85. doi:10.1016/S1470-2045(14)70240-2. PMID 24974051. 
  10. ^ Agarwal N, Di Lorenzo G, Sonpavde G, Bellmunt J (2014). "New agents for prostate cancer". Ann. Oncol. 25 (9): 1700–9. doi:10.1093/annonc/mdu038. PMID 24658665. 
  11. ^ https://chem.nlm.nih.gov/chemidplus/rn/1297538-32-9

External links[edit]