Chemistry:Apalutamide

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Short description: Chemical compound
Apalutamide
Apalutamide.svg
Apalutamide molecule ball.png
Clinical data
Trade namesErleada, others
Other namesARN-509; JNJ-56021927; JNJ-927; A52
AHFS/Drugs.comMonograph
MedlinePlusa618018
License data
Pregnancy
category
Routes of
administration		By mouth[2]
Drug classNonsteroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability100%[2]
Protein bindingApalutamide: 96%[2]
NDMA: 95%[2]
MetabolismLiver (CYP2C8, CYP3A4)[2]
Metabolites• NDMA[2]
Elimination half-lifeApalutamide: 3–4 days (at steady-state)[5][2]
ExcretionUrine: 65%[2]
Feces: 24%[2]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC21H15F4N5O2S
Molar mass477.44 g·mol−1
3D model (JSmol)

Apalutamide, sold under the brand name Erleada among others, is a nonsteroidal antiandrogen (NSAA) medication which is used in the treatment of prostate cancer.[2][6][7][8][9] It is specifically indicated for use in conjunction with castration in the treatment of non-metastatic castration-resistant prostate cancer (NM-CRPC).[2][10][11] It is taken by mouth.[2][6]

Side effects of apalutamide when added to castration include fatigue, nausea, abdominal pain, diarrhea, high blood pressure, rash, falls, bone fractures, and an underactive thyroid.[2][12][13][6][8] Rarely, it can cause seizures.[2][6] The medication has a high potential for drug interactions.[2][6] Apalutamide is an antiandrogen, and acts as an antagonist of the androgen receptor, the biological target of androgens like testosterone and dihydrotestosterone.[2][6][9] In doing so, it prevents the effects of these hormones in the prostate gland and elsewhere in the body.[2][6][9]

Apalutamide was first described in 2007, and was approved for the treatment of prostate cancer in February 2018.[10][11][6][14] It was the first medication to be approved specifically for the treatment of NM-CRPC.[2][6][11]


Medical uses

Apalutamide is used in conjunction with castration, either via bilateral orchiectomy or gonadotropin-releasing hormone analogue (GnRH analogue) therapy, as a method of androgen deprivation therapy in the treatment of NM-CRPC.[2][15][16][17] It is also a promising potential treatment for metastatic castration-resistant prostate cancer (mCRPC), which the NSAA enzalutamide and the androgen synthesis inhibitor abiraterone acetate are used to treat.[8]

Available forms

Apalutamide is provided in the form of 60 mg oral tablets.[2] It is taken at a dosage of 240 mg once per day (four tablets) when used in the treatment of NM-CRPC.[2]

Contraindications

Contraindications of apalutamide include pregnancy and a history of or susceptibility to seizures.[2]

Side effects

Apalutamide has been found to be well tolerated in clinical trials,[18][15] with the most common side effects reported when added to surgical or medical castration including fatigue, nausea, abdominal pain, and diarrhea.[12][13][19] Other side effects have included rash, falls and bone fractures, and hypothyroidism, as well as seizures (in 0.2%), among others.[2][6][11] Apalutamide is an expected teratogen and has a theoretical risk of birth defects in male infants if taken by women during pregnancy.[2] It may impair male fertility.[2] When used as a monotherapy (i.e., without surgical or medical castration) in men, NSAAs are known to produce additional, estrogenic side effects like breast tenderness, gynecomastia, and feminization in general by increasing estradiol levels.[20] Similarly to the related second-generation NSAA enzalutamide but unlike first-generation NSAAs like flutamide and bicalutamide, elevated liver enzymes and hepatotoxicity have not been reported with apalutamide.[2] Case reports of rare interstitial lung disease with apalutamide exist similarly to with first-generation NSAAs however.[21][22][23]

Overdose

There is no known antidote for overdose of apalutamide.[2] General supportive measures should be undertaken until clinical toxicity, if any, diminishes or resolves.[2]

Interactions

Apalutamide has a high potential for drug interactions.[2] In terms of effects of apalutamide on other drugs, the exposure of substrates of CYP3A4, CYP2C19, CYP2C9, UDP-glucuronosyltransferase, P-glycoprotein, ABCG2, or OATP1B1 may be reduced to varying extents.[2] In terms of effects of other drugs on apalutamide, strong CYP2C8 or CYP3A4 inhibitors may increase levels of apalutamide or its major active metabolite N-desmethylapalutamide, while mild to moderate CYP2C8 or CYP3A4 inhibitors are not expected to affect their exposure.[2]

Pharmacology

Pharmacodynamics

Antiandrogenic activity

Apalutamide acts as a selective competitive silent antagonist of the androgen receptor (AR), via the ligand-binding domain, and hence is an antiandrogen.[6][9][12][15] It is similar both structurally and pharmacologically to the second-generation NSAA enzalutamide,[18][24] but shows some advantages, including higher antiandrogenic activity as well as several-fold reduced central nervous system distribution.[9][12][15] The latter difference may reduce its comparative risk of seizures and other central side effects.[9][12][15] Apalutamide has 5- to 10-fold greater affinity for the AR than bicalutamide, a first-generation NSAA.[17][16]

The acquired F876L mutation of the AR identified in advanced prostate cancer cells has been found to confer resistance to both enzalutamide and apalutamide.[25][26] A newer NSAA, darolutamide, is not affected by this mutation, nor has it been found to be affected by any other tested/well-known AR mutations.[27] Apalutamide may be effective in a subset of prostate cancer patients with acquired resistance to abiraterone acetate.[18]

Other activities

Apalutamide shows potent induction potential of cytochrome P450 enzymes similarly to enzalutamide.[2][28][29] It is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9, as well as an inducer of UDP-glucuronosyltransferase.[2] In addition, apalutamide is an inducer of P-glycoprotein, ABCG2, and OATP1B1.[2]

Apalutamide binds weakly to and inhibits the GABAA receptor in vitro similarly to enzalutamide (IC50 = 3.0 and 2.7 μM, respectively),[30] but due to its relatively lower central concentrations, may have a lower risk of seizures in comparison.[9][12][19]

Apalutamide has been found to significantly and concentration-dependently increase QT interval.[2]

Pharmacokinetics

The mean absolute oral bioavailability of apalutamide is 100%.[2] Mean peak levels of apalutamide occur 2 hours following administration, with a range of 1 to 5 hours.[2] Food delays the median time to peak levels of apalutamide by approximately 2 hours, with no significant changes in the peak levels themselves or in area-under-curve levels.[2] Steady-state levels of apalutamide are achieved following 4 weeks of administration, with an approximate 5-fold accumulation.[2] Peak concentrations for 160 mg/day apalutamide at steady-state are 6.0 μg/mL (12.5 μmol/L),[2] relative to peak levels of 16.6 μg/mL (35.7 μmol/L) for 160 mg/day enzalutamide and mean (R)-bicalutamide levels of 21.6 μg/mL (50.2 μmol/L) for 150 mg/day bicalutamide.[31][32] The mean volume of distribution of apalutamide at steady-state is approximately 276 L.[2] The plasma protein binding of apalutamide is 96%, while that of its major metabolite N-desmethylapalutamide is 95%, both irrespective of concentration.[2]

Apalutamide is metabolized in the liver by CYP2C8 and CYP3A4.[2] A major active metabolite, N-desmethylapalutamide, is formed by these enzymes, with similar contribution of each of these enzymes to its formation at steady-state.[2] Following a single oral dose of 200 mg apalutamide, apalutamide represented 45% and N-desmethylapalutamide 44% of total area-under-curve levels.[2] The mean elimination half-life of apalutamide at steady-state is 3 to 4 days.[2][5] Fluctuations in apalutamide exposure are low and levels are stable throughout the day, with mean peak-to-trough ratios of 1.63 for apalutamide and 1.27–1.3 for N-desmethylapalutamide.[2] After a single dose of apalutamide, its clearance rate (CL/F) was 1.3 L/h, while its clearance rate increased to 2.0 L/h at steady-state.[6] This change is considered to be likely due to CYP3A4 auto-induction.[6] Approximately 65% of apalutamide is excreted in urine (1.2% as unchanged apalutamide and 2.7% as N-desmethylapalutamide) while 24% is excreted in feces (1.5% as unchanged apalutamide and 2% as N-desmethylapalutamide).[2]

Chemistry

Apalutamide is a structural analogue of enzalutamide and RD-162.[17][33] It is a pyridyl variant of RD-162. Enzalutamide and RD-162 were derived from the nonsteroidal androgen RU-59063, which itself was derived from the first-generation NSAA nilutamide and by extension from flutamide.[34]

Chemical structures of apalutamide and its predecessors

History

Apalutamide was originated by the University of California system and was developed primarily by Janssen Research & Development, a division of Johnson & Johnson.[35] It was first described in the literature in a United States patent application that was published in November 2007 and in another that was submitted in July 2010.[14][36] A March 2012 publication described the discovery and development of apalutamide.[9] A phase I clinical trial of apalutamide was completed by March 2012, and the results of this study were published in 2013.[9][37] Information on phase III clinical studies, including ATLAS, SPARTAN, and TITAN, was published between 2014 and 2016.[38][39][40] Positive results for phase III trials were first described in 2017, and Janssen submitted a New Drug Application for apalutamide to the United States Food and Drug Administration on 11 October 2017.[41] Apalutamide was approved by the Food and Drug Administration in the United States, under the brand name Erleada, for the treatment of NM-CRPC on 14 February 2018.[10][11] It was subsequently approved in Canada , the European Union, and Australia .[42][4]

Society and culture

Generic names

Apalutamide is the generic name of the drug and its INN.[43][42] It is also known by its developmental code names ARN-509 and JNJ-56021927.[35][6]

Brand names

Apalutamide is marketed under the brand names Erleada and Erlyand.[2][10][11][42]

Availability

Apalutamide is available in the United States , Canada , the European Union, and Australia .[2][10][11][42][4]

References

  1. ↑ "Apalutamide (Erleada) Use During Pregnancy". 20 July 2020. https://www.drugs.com/pregnancy/apalutamide.html. 
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 2.15 2.16 2.17 2.18 2.19 2.20 2.21 2.22 2.23 2.24 2.25 2.26 2.27 2.28 2.29 2.30 2.31 2.32 2.33 2.34 2.35 2.36 2.37 2.38 2.39 2.40 2.41 2.42 2.43 2.44 2.45 2.46 2.47 2.48 2.49 2.50 "Erleada- apalutamide tablet, film coated". 27 October 2020. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d1cda4f7-cb33-46ea-b9ac-431f6452b1a5. 
  3. ↑ "PRODUCT MONOGRAPH INCLUDING PATIENT MEDICATION INFORMATION" (in en). Janssen Inc.. 6 July 2021. https://pdf.hres.ca/dpd_pm/00062050.PDF. 
  4. ↑ 4.0 4.1 4.2 "Erleada EPAR" (in an). 13 November 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/erleada. 
  5. ↑ 5.0 5.1 "Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer". Journal of Clinical Oncology 31 (28): 3525–30. October 2013. doi:10.1200/JCO.2013.50.1684. PMID 24002508. 
  6. ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 "Apalutamide: First Global Approval". Drugs 78 (6): 699–705. April 2018. doi:10.1007/s40265-018-0900-z. PMID 29626324. 
  7. ↑ "Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: evidence to date". OncoTargets Ther 11: 2141–2147. 2018. doi:10.2147/OTT.S147168. PMID 29695920. 
  8. ↑ 8.0 8.1 8.2 "Apalutamide: The established and emerging roles in the treatment of advanced prostate cancer". Expert Opin Investig Drugs 27 (6): 553–559. June 2018. doi:10.1080/13543784.2018.1484107. PMID 29856649. 
  9. ↑ 9.0 9.1 9.2 9.3 9.4 9.5 9.6 9.7 9.8 "ARN-509: a novel antiandrogen for prostate cancer treatment". Cancer Research 72 (6): 1494–503. March 2012. doi:10.1158/0008-5472.CAN-11-3948. PMID 22266222. 
  10. ↑ 10.0 10.1 10.2 10.3 10.4 "FDA approves new treatment for a certain type of prostate cancer using novel clinical trial endpoint". 24 March 2020. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm596768.htm. 
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 "FDA Approves Apalutamide for Nonmetastatic Prostate Cancer". https://www.medscape.com/viewarticle/892708. 
  12. ↑ 12.0 12.1 12.2 12.3 12.4 12.5 "Abiraterone and other novel androgen-directed strategies for the treatment of prostate cancer: a new era of hormonal therapies is born". Therapeutic Advances in Urology 4 (4): 167–78. August 2012. doi:10.1177/1756287212452196. PMID 22852027. 
  13. ↑ 13.0 13.1 "Targeting the androgen receptor in the management of castration-resistant prostate cancer: rationale, progress, and future directions". Current Oncology 19 (Suppl 3): S22-31. December 2012. doi:10.3747/co.19.1281. PMID 23355790. 
  14. ↑ 14.0 14.1 Jung ME, Sawyers CL, Ouk S, Tran C, Wongvipat J, "Androgen receptor modulator for the treatment of prostate cancer and androgen receptor-associated diseases", WO patent 2007126765, published 8 November 2007, assigned to The Regents Of The University Of California.
  15. ↑ 15.0 15.1 15.2 15.3 15.4 "Androgen receptor antagonists in castration-resistant prostate cancer". Cancer Journal 19 (1): 43–9. 2013. doi:10.1097/PPO.0b013e318282635a. PMID 23337756. 
  16. ↑ 16.0 16.1 "Quo vadis: advanced prostate cancer-clinical care and clinical research in the era of multiple androgen receptor-directed therapies". Cancer 121 (3): 361–71. February 2015. doi:10.1002/cncr.28929. PMID 25236176. 
  17. ↑ 17.0 17.1 17.2 "Androgen Receptor Antagonists in the Treatment of Prostate Cancer". Clinical Immunology, Endocrine & Metabolic Drugs 1 (1): 11–19. June 2014. doi:10.2174/22127070114019990002. ISSN 2212-7070. 
  18. ↑ 18.0 18.1 18.2 "Emerging molecularly targeted therapies in castration refractory prostate cancer". Prostate Cancer 2013: 981684. 2013. doi:10.1155/2013/981684. PMID 23819055. 
  19. ↑ 19.0 19.1 "Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer". Cancer Biology & Therapy 15 (2): 149–55. February 2014. doi:10.4161/cbt.26724. PMID 24100689. 
  20. ↑ "The role of antiandrogen monotherapy in the treatment of prostate cancer". BJU Int. 91 (5): 455–61. March 2003. doi:10.1046/j.1464-410x.2003.04026.x. PMID 12603397. 
  21. ↑ "Interstitial lung disease induced by apalutamide therapy for castration-resistant prostate cancer: A report of a rare case". IJU Case Rep 5 (3): 153–155. May 2022. doi:10.1002/iju5.12420. PMID 35509772. 
  22. ↑ "Apalutamide-induced severe interstitial lung disease: A report of two cases from Japan". Respir Investig 59 (5): 700–705. September 2021. doi:10.1016/j.resinv.2021.05.006. PMID 34144936. 
  23. ↑ "Analysis of adverse event of interstitial lung disease in men with prostate cancer receiving hormone therapy using the Food and Drug Administration Adverse Event Reporting System". Br J Clin Pharmacol 89 (2): 440–448. March 2022. doi:10.1111/bcp.15336. PMID 35349180. 
  24. ↑ Pharmacology and Therapeutics of Constitutively Active Receptors. Elsevier Science. 11 June 2014. pp. 351–. ISBN 978-0-12-417206-7. https://books.google.com/books?id=crNZAwAAQBAJ&pg=PA351. "ARN-509 is related structurally to enzalutamide with greater in vivo activity in CRPC xenograft models (Clegg et al., 2012)." 
  25. ↑ "A clinically relevant androgen receptor mutation confers resistance to second-generation antiandrogens enzalutamide and ARN-509". Cancer Discovery 3 (9): 1020–9. September 2013. doi:10.1158/2159-8290.CD-13-0226. PMID 23779130. 
  26. ↑ "Resistance emerges to second-generation antiandrogens in prostate cancer". Cancer Discovery 3 (9): 971–4. September 2013. doi:10.1158/2159-8290.CD-13-0405. PMID 24019330. 
  27. ↑ "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Scientific Reports 5: 12007. July 2015. doi:10.1038/srep12007. PMID 26137992. Bibcode: 2015NatSR...512007M. 
  28. ↑ "ODM-201: a new-generation androgen receptor inhibitor in castration-resistant prostate cancer". Expert Review of Anticancer Therapy 15 (9): 1007–17. 2015. doi:10.1586/14737140.2015.1081566. PMID 26313416. 
  29. ↑ "Preclinical Development of ONC1-13B, Novel Antiandrogen for Prostate Cancer Treatment". Journal of Cancer 5 (2): 133–42. 2014. doi:10.7150/jca.7773. PMID 24494031. 
  30. ↑ "ARN-509: a novel antiandrogen for prostate cancer treatment". Cancer Research 72 (6): 1494–503. March 2012. doi:10.1158/0008-5472.CAN-11-3948. PMID 22266222. 
  31. ↑ "Reference at www.accessdata.fda.gov". https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/203415s011lbl.pdf. 
  32. ↑ "Bicalutamide: clinical pharmacokinetics and metabolism". Clin Pharmacokinet 43 (13): 855–78. 2004. doi:10.2165/00003088-200443130-00003. PMID 15509184. 
  33. ↑ "Development of a second-generation antiandrogen for treatment of advanced prostate cancer". Science 324 (5928): 787–90. 2009. doi:10.1126/science.1168175. PMID 19359544. Bibcode: 2009Sci...324..787T. 
  34. ↑ "Developments in nonsteroidal antiandrogens targeting the androgen receptor". ChemMedChem 5 (10): 1651–61. 2010. doi:10.1002/cmdc.201000259. PMID 20853390. 
  35. ↑ 35.0 35.1 "Apalutamide - Janssen Research and Development". AdisInsight. Springer Nature Switzerland AG. http://adisinsight.springer.com/drugs/800032695. 
  36. ↑ Ouerfelli O, Dilhas A, Yang G, Zhao H, "Synthesis of thiohydantoins", US patent 20100190991, issued 11 June 2013, assigned to Sloan Kettering Institute for Cancer Research.
  37. ↑ "Phase I study of ARN-509, a novel antiandrogen, in the treatment of castration-resistant prostate cancer". Journal of Clinical Oncology 31 (28): 3525–3530. October 2013. doi:10.1200/JCO.2013.50.1684. PMID 24002508. 
  38. ↑ "A randomized double-blind, comparative study of ARN-509 plus androgen deprivation therapy (ADT) versus ADT alone in nonmetastatic castration-resistant prostate cancer (M0-CRPC): The SPARTAN trial.". 2014 ASCO Annual Meeting. doi:10.1200/jco.2014.32.15_suppl.tps5100. 
  39. ↑ "ATLAS: A phase 3 trial evaluating the efficacy of apalutamide (ARN-509) in patients with high-risk localized or locally advanced prostate cancer receiving primary radiation therapy". Annals of Oncology 27 (suppl_6): vi263. 2016. doi:10.1093/annonc/mdw372.52. ISSN 0923-7534. 
  40. ↑ "TITAN: A randomized, double-blind, placebo-controlled, phase 3 trial of apalutamide (ARN-509) plus androgen deprivation therapy (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC)". Annals of Oncology 27 (suppl_6): vi265. 2016. doi:10.1093/annonc/mdw372.54. ISSN 0923-7534. 
  41. ↑ "Janssen Submits New Drug Application to U.S. FDA for Apalutamide (ARN-509) to Treat Men with Non-Metastatic Castration-Resistant Prostate Cancer". PR Newswire (Press release).
  42. ↑ 42.0 42.1 42.2 42.3 "Erleada (Apalutamide): Side Effects, Dosage & Uses". Drugs.com. https://www.drugs.com/international/apalutamide.html. 
  43. ↑ "International Nonproprietary Names for Pharmaceutical Substances (INN)". WHO Drug Information 29 (2). 2015. https://www.who.int/medicines/publications/druginformation/innlists/PL113.pdf. 

Further reading

External links

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