Darolutamide

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Darolutamide
ODM-201.svg
Darolutamide molecule ball.png
Clinical data
Trade namesNubeqa
Other namesDarramamide; ODM-201; BAY-1841788
Routes of
administration
By mouth
Drug classNonsteroidal antiandrogen
ATC code
Pharmacokinetic data
Bioavailability≤30%[1]
Protein bindingDarolutamide: 92%[1]
Ketodarolutamide: 99.8%[1]
MetabolismDehydrogenation (CYP3A4), glucuronidation (UGT1A9, UGT1A1)[1]
MetabolitesKetodarolutamide[1][2]
Elimination half-life16–20 hours[1][2]
ExcretionUrine: 63.4%[1]
Feces: 32.4%[1]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ECHA InfoCard100.264.885 Edit this at Wikidata
Chemical and physical data
FormulaC19H19ClN6O2
Molar mass398.85 g·mol−1
3D model (JSmol)
  (verify)

Darolutamide, sold under the brand name Nubeqa, is an antiandrogen medication which is used in the treatment of prostate cancer in men.[1][3][4][5] It is specifically approved to treat non-metastatic castration-resistant prostate cancer (nmCRPC) in conjunction with surgical or medical castration.[1][3] The medication is taken by mouth twice per day with food.[1]

Side effects of darolutamide added to castration may include fatigue, asthenia, pain in the arms and legs, and rash.[1] Darolutamide is a nonsteroidal antiandrogen (NSAA), and acts as a selective antagonist of the androgen receptor (AR).[1][4][5] It has been referred to as a second- or third-generation NSAA.[6][7]

Darolutamide was patented in 2011 and was approved for medical use in July 2019.[8][3][9]

Medical uses[edit]

Darolutamide is approved for use concurrently with a gonadotropin-releasing hormone (GnRH) agonist or antagonist or bilateral orchiectomy in the treatment of non-metastatic castration-resistant prostate cancer (nmCRPC) in men.[4][5] It is used at a dosage of 600 mg orally twice per day (1,200 mg/day total) with food.[1] In individuals with severe renal impairment or moderate hepatic impairment, darolutamide is used at a dosage of 300 mg orally twice per day (600 mg/day total) with food.[1] No dosage adjustment is needed for mild to moderate renal impairment or mild hepatic impairment, whereas appropriate dosage adjustment for end-stage kidney disease and severe hepatic impairment is unknown.[1]

Available forms[edit]

Darolutamide is provided in the form of 300 mg oral film-coated tablets.[1]

Contraindications[edit]

Darolutamide has no contraindications in men.[1] However, the medication may have teratogenic effects in male fetuses due to its antiandrogenic effects and hence should not be used by women who are pregnant.[1]

Side effects[edit]

The most common side effects of darolutamide in clinical trials (≥2% incidence) in castrated men included fatigue and asthenia (16% vs. 11% for placebo), pain in extremities (6% vs. 3% for placebo), and rash (3% vs. 1% for placebo).[1] Darolutamide was also associated with higher incidences of ischemic heart disease (4.0% vs. 3.4% for placebo) and heart failure (2.1% vs. 0.9% for placebo).[1] In terms of laboratory test abnormalities, darolutamide was associated with decreased neutrophil count (20% vs. 9% for placebo), increased aspartate aminotransferase (AST) (23% vs. 14% for placebo; Grade 3–4: 0.5% vs. 0.2% for placebo), and increased bilirubin (16% vs. 7% for placebo).[1] In the clinical studies, 88% of patients treated with darolutamide were age 65 years or older.[1]

No seizures have been observed with darolutamide in clinical trials.[10][11] Darolutamide is an expected teratogen and has a theoretical risk of birth defects in male infants if taken by women during pregnancy.[1] It may impair male fertility.[1] When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to produce feminizing breast changes including breast tenderness and gynecomastia.[12]

Overdose[edit]

Darolutamide has been studied at a dosage of up to 1,800 mg/day in clinical trials.[1] There were no dose-limiting toxicities seen at this dosage.[1] Due to its saturable absorption and lack of acute toxicity, overdose of darolutamide is not expected to result in systemic toxicity in people with intact hepatic and renal function.[1] There is no specific antidote for overdose of darolutamide.[1] In the event of darolutamide overdose, if there is no toxicity, treatment can be continued as normal.[1] If there is suspicion of toxicity, general supportive measures should be undertaken until clinical toxicity has decreased or resolved and then treatment may be continued.[1]

Interactions[edit]

Combined P-glycoprotein and strong or moderate CYP3A4 inducers such as rifampicin may decrease exposure to darolutamide, while combined P-glycoprotein and strong CYP3A4 inhibitors such as itraconazole may increase exposure to darolutamide.[1] Darolutamide is an inhibitor of the breast cancer resistance protein (BCRP) transporter and can increase exposure to substrates for this protein such as rosuvastatin.[1] It has been found to increase exposure to rosuvastatin by approximately 5-fold.[1]

Pharmacology[edit]

Pharmacodynamics[edit]

Darolutamide is second- or third-generation nonsteroidal antiandrogen (NSAA).[6][7] It acts as a selective competitive silent antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT).[1] Its affinity (Ki) for the AR is 11 nM and its functional inhibition (IC50) of the AR is 26 nM.[5] The major metabolite of darolutamide, ketodarolutamide, has similar antiandrogenic activity relative to darolutamide (Ki = 8 nM; IC50 = 38 nM).[1][5] 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.[1]

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.[1][additional citation(s) needed] 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.[13][14][2]

Darolutamide shows some advantages in comparison to enzalutamide and apalutamide, two other second-generation NSAAs.[5] 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.[5] In accordance with its diminished central penetration, darolutamide does not appear to increase testosterone levels.[5] 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.[5] The medication shows higher affinity and inhibitory potency at the AR relative to enzalutamide and apalutamide in vitro (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).[5]

Darolutamide inhibits the organic anion transporting polypeptide (OATP) transporters OATP1B1 and OATP1B3 in vitro.[1] It shows no inhibition or induction of cytochrome P450 enzymes (CYP1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, 3A4) at clinically relevant concentrations.[15] Similarly, darolutamide shows no inhibition of a variety of other transporters (P-glycoprotein, MRP2, BSEP, OATs, OCTs, MATEs, OATP2B1, NTCP) at therapeutic concentrations.[1][16]

Pharmacokinetics[edit]

The absolute bioavailability of darolutamide with oral administration of a single 300-mg dose without food is approximately 30%.[1] The bioavailability of darolutamide is increased by about 2- to 2.5-fold when administered with food, with a similar increase in exposure occurring for ketodarolutamide.[1] Exposure to darolutamide and ketodarolutamide increases in a nearly linear or dose-proportional manner across a dose range of 100 to 700 mg (or about 0.17- to 1.17-fold the recommended 600-mg dosage).[1] No further increase in exposure to darolutamide was observed at a dosage of darolutamide of 900 mg twice per day (or 1.5 times the recommended 600-mg dosage), indicating a saturation of absorption at doses above 700 mg.[1] Following a single 600-mg dose of darolutamide, peak levels of darolutamide occur after approximately 4 hours.[1] 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.[1] 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.[1] Total exposure to ketodarolutamide is approximately 1.7-fold that of darolutamide.[1]

The volume of distribution of darolutamide with intravenous administration is 119 L.[1] The plasma protein binding of darolutamide is 92%, with 8% circulating freely, and of ketodarolutamide is 99.8%, with 0.2% circulating unbound.[1] As such, free levels of darolutamide in the circulation are about 40-fold higher than those of ketodarolutamide.[1] Both darolutamide and ketodarolutamide are bound mainly to albumin.[1] Darolutamide and ketodarolutamide appear to negligibly cross the blood–brain barrier both in mice and humans.[5]

Darolutamide is primarily metabolized into ketodarolutamide via dehydrogenation by CYP3A4 in the liver.[1] The medication is also conjugated via glucuronidation by UGT1A9 and UGT1A1.[1] The elimination half-life of darolutamide and ketodarolutamide has been reported to be approximately 20 hours.[1] 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.[2] The elimination half-life of darolutamide is far shorter than that of enzalutamide (e.g., 1.6 hours vs. 18.3 hours in mice).[14] The clearance of darolutamide following intravenous administration is 116 mL/min.[1]

After a single oral dose of darolutamide, more than 95% of the dose is excreted in urine and feces within one week following administration.[1] 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.[1]

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.[1] 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.[1] In non-nmCRPC individuals with moderate hepatic impairment, darolutamide exposure was increased by about 1.9-fold compared to healthy controls.[1] The pharmacokinetics of darolutamide have not been assessed in end-stage kidney disease or severe hepatic impairment.[1]

Chemistry[edit]

Darolutamide is a nonsteroidal compound and is structurally distinct from other marketed NSAAs, including enzalutamide and apalutamide.[14]

History[edit]

Darolutamide was developed by Orion Corporation and Bayer HealthCare.[3] Orion Corporation applied for a patent on darolutamide in October 2010, and this patent was published in May 2011.[8] Darolutamide entered phase I clinical trials in April 2011,[2][17] with the results of the first clinical study of darolutamide initially published in 2012.[18] The United States Food and Drug Administration approved darolutamide in July 2019 under the agency's Priority Review designation.[3][9]

Society and culture[edit]

Generic names[edit]

Darolutamide is the generic name of the drug and its INN and USAN.[19] It is also known by its developmental code names ODM-201 and BAY-1841788.[3]

Brand names[edit]

Darolutamide is marketed under the brand name Nubeqa.[1][3]

Availability[edit]

Darolutamide is available in the United States.[1][3]

Research[edit]

Darolutamide monotherapy is being studied in comparison to androgen deprivation therapy with GnRH agonist or antagonist monotherapy in men with treatment-naive prostate cancer.[3][13][20] As of 2018, it is entering a phase II clinical trial for this indication.[3][13][20] This study is expected for completion in 2021 or 2022.[21]

Darolutamide is in phase II clinical trials for the treatment of breast cancer in women.[3]

References[edit]

  1. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai aj ak al am an ao ap aq ar as at au av aw ax ay az ba bb bc bd be bf bg bh bi bj bk bl https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/212099Orig1s000lbl.pdf
  2. ^ 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.
  3. ^ a b c d e f g h i j k http://adisinsight.springer.com/drugs/800033671
  4. ^ a b c 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 4673554. PMID 26313416.
  5. ^ 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 4490394. PMID 26137992.
  6. ^ a b Shore, Neal D. (2017). "Darolutamide (ODM-201) for the treatment of prostate cancer". Expert Opinion on Pharmacotherapy. 18 (9): 945–952. doi:10.1080/14656566.2017.1329820. ISSN 1465-6566.
  7. ^ a b Crawford, E. David; Schellhammer, Paul F.; McLeod, David G.; Moul, Judd W.; Higano, Celestia S.; Shore, Neal; Denis, Louis; Iversen, Peter; Eisenberger, Mario A.; Labrie, Fernand (2018). "Androgen Receptor Targeted Treatments of Prostate Cancer: 35 Years of Progress with Antiandrogens". Journal of Urology. 200 (5): 956–966. doi:10.1016/j.juro.2018.04.083. ISSN 0022-5347.
  8. ^ a b https://patents.google.com/patent/WO2011051540A1
  9. ^ a b https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-darolutamide-non-metastatic-castration-resistant-prostate-cancer
  10. ^ 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.
  11. ^ 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.
  12. ^ Anderson J (March 2003). "The role of antiandrogen monotherapy in the treatment of prostate cancer". BJU Int. 91 (5): 455–61. doi:10.1046/j.1464-410x.2003.04026.x. PMID 12603397.
  13. ^ a b c Fizazi, Karim; Smith, Matthew R.; Tombal, Bertrand (2018). "Clinical Development of Darolutamide: A Novel Androgen Receptor Antagonist for the Treatment of Prostate Cancer". Clinical Genitourinary Cancer. 16 (5): 332–340. doi:10.1016/j.clgc.2018.07.017. ISSN 1558-7673.
  14. ^ a b c 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 4490394. PMID 26137992.
  15. ^ https://meetinglibrary.asco.org/record/89078/edbook#fulltext
  16. ^ Zurth, Christian; Graudenz, Kristina; Denner, Karsten; Korjamo, Timo; Fricke, Robert; Wilkinson, Gary; Seitz, Friedeborg; Prien, Olaf (2019). "Drug-drug interaction (DDI) of darolutamide with cytochrome P450 (CYP) and P-glycoprotein (P-gp) substrates: Results from clinical and in vitro studies". Journal of Clinical Oncology. 37 (7_suppl): 297–297. doi:10.1200/JCO.2019.37.7_suppl.297. ISSN 0732-183X.
  17. ^ James L. Gulley (20 December 2011). Prostate Cancer. Demos Medical Publishing. pp. 513–. ISBN 978-1-936287-46-8.
  18. ^ Leibowitz–Amit, R.; Joshua, A. (2012). "Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress, and future directions". Current Oncology. 19 (S3). doi:10.3747/co.19.1281. ISSN 1198-0052.
  19. ^ https://chem.nlm.nih.gov/chemidplus/rn/1297538-32-9
  20. ^ a b Tombal, Bertrand F.; Gillessen, Silke; Loriot, Yohann; Marreaud, Sandrine; Collette, Laurence; Saad, Fred (2018). "Intergroup study EORTC-1532-gucg: A phase 2 randomized open-label study of oral darolutamide (ODM-201) vs. androgen deprivation therapy (ADT) with LHRH agonists or antagonist in men with hormone naive prostate cancer (PCa)". Journal of Clinical Oncology. 36 (6_suppl): TPS406–TPS406. doi:10.1200/JCO.2018.36.6_suppl.TPS406. ISSN 0732-183X.
  21. ^ https://adisinsight.springer.com/trials/700279055

External links[edit]