Nilutamide

Nilutamide (INN, USAN, BAN)
Clinical data
Pronunciation nye-LOO-tah-mide[1]
Trade names Nilandron, Anandron
AHFS/Drugs.com Monograph
MedlinePlus a697044
Pregnancy
category
Routes of
administration		 Oral[3]
ATC code L02BB02 (WHO)
Legal status
Legal status
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability Good[3]
Protein binding 80–84%[4]
Metabolism Liver: CYP2C19, FMO[3][4]
Metabolites At least 5, some active[4][5]
Biological half-life 23–87 hours (mean 56 hours, or about 2 days)[6]
Excretion Urine (62%);
Feces (<10%)[3][4]
Identifiers
Synonyms RU-23908
CAS Number 63612-50-0 YesY
PubChem (CID) 4493
IUPHAR/BPS 2864
DrugBank DB00665 YesY
ChemSpider 4337 YesY
UNII 51G6I8B902 YesY
KEGG D00965 YesY
ChEBI CHEBI:7573 YesY
ChEMBL CHEMBL1274 YesY
ECHA InfoCard 100.153.268
Chemical and physical data
Formula C12H10F3N3O4
Molar mass 317.221 g/mol
3D model (Jmol) Interactive image
  (verify)

Nilutamide (brand names Nilandron (US), Anandron (CA)) is a synthetic, non-steroidal antiandrogen (NSAA) used in the treatment of advanced-stage (metastatic) prostate cancer.[7][8][9] It was developed by Roussel, first introduced in 1987 (in Europe)[7][6] and was the second NSAA to be marketed, with flutamide preceding it and bicalutamide following it in 1995.[9][10] It was not introduced until 1996 in the United States.[11][12] Because most prostate cancer cells rely on activation of the androgen receptor (AR) for growth and survival, nilutamide can slow the progression of the disease and extend life in men with prostate cancer.[13]

Nilutamide shows unique and unfavorable tolerability and toxicity profiles, most importantly a high incidence of interstitial pneumonitis (which can progress to pulmonary fibrosis, a potentially fatal condition),[14] and this has limited its clinical use.[9][15][16] From a safety standpoint, bicalutamide is clinically preferred not only over nilutamide (due primarily to its risk of interstitial pneumonitis) but also flutamide (due to its high risk of hepatotoxicity) in choice of NSAA.[17]

Indications

Prostate cancer

Nilutamide is used in prostate cancer in combination with a gonadotropin-releasing hormone (GnRH) analogue at a dosage of 300 mg/day (150 mg twice daily) for the first 4 weeks of treatment, and 150 mg/day thereafter.[16][18] It is not indicated as a monotherapy in prostate cancer.[16]

Transgender hormone therapy

Nilutamide has been researched and used as a component of hormone replacement therapy in transgender women.[13][19] It has been assessed in at least five small clinical studies for this purpose in treatment-naive subjects.[19][20][21][22][23][24] In these studies, nilutamide monotherapy at a dosage of 300 mg/day, induced observable signs of clinical feminization in young transgender women (age range 19–33 years) within 8 weeks,[21] including breast development, decreased body hair (though not facial hair),[20] decreased morning erections and sex drive,[22] and positive psychological and emotional changes.[22][25] Signs of breast development occurred in all subjects within 6 weeks and were associated with increased nipple sensitivity,[24][21][22] and along with decreased hair growth, were the earliest sign of feminization.[21]

Nilutamide did not change the size of the prostate gland (which is the same as with high-dosage cyproterone acetate and ethinyl estradiol treatment for as long as 18 months), but was found to alter its histology, including increased stromal tissue with a significant reduction in acini and atrophic epithelial cells, indicating glandular atrophy.[23][24] In addition, readily apparent histological changes were observed in the testes, including a reduction in tubular and interstitial cells.[23]

Nilutamide was found to more than double luteinizing hormone (LH) and testosterone levels and to triple estradiol levels.[20][21][23] In contrast, follicle-stimulating hormone levels remained unchanged.[21][23] A slight but significant increase in prolactin levels was observed, and levels of sex hormone-binding globulin increased as well.[21][23] The addition of ethinyl estradiol to nilutamide therapy after 8 weeks abolished the increase in LH, testosterone, and estradiol levels and dramatically suppressed testosterone levels, into the castrate range.[20][21] Both nilutamide alone and the combination of nilutamide and estrogen were regarded as resulting in effective and favorable antiandrogen action and feminization in transgender women.[20][21]

Tolerability and safety

General side effects of NSAAs, including nilutamide, include gynecomastia (40–80%), breast pain/tenderness, hot flashes (67%), depression, fatigue, sexual dysfunction (including loss of libido and erectile dysfunction), decreased muscle mass, and decreased bone mass with an associated increase in fractures.[26][27][28] Also, nausea (24–27%), vomiting, constipation (20%), and insomnia (16%) may occur with nilutamide.

Relative to other NSAAs, nilutamide has been uniquely associated with mild and reversible visual disturbances (31–58%) including delayed ocular adaptation to darkness and impaired color vision,[29] a disulfiram-like[26] alcohol intolerance (19%), interstitial pneumonitis (0.77–2.4%)[17][30][31] (which can result in dyspnea (1%) as a secondary effect and can progress to pulmonary fibrosis),[32] and hepatitis (1%), and has a higher incidence of nausea and vomiting compared to other NSAAs.[9][16][28][33] The incidence of interstitial pneumonitis with nilutamide has been found to be much higher in Japanese patients (12.6%), warranting particular caution in Asian individuals.[34][35] There is a case report of simultaneous liver and lung toxicity in a nilutamide-treated patient.[36]

There is also a risk of hepatoxicity with nilutamide, though occurrence is very rare and the risk is significantly less than with flutamide.[37][38] The incidence of abnormal liver function tests (e.g., elevated liver enzymes) is 2–3% with nilutamide, relative to 42–62% for flutamide.[39][6] Fulminant hepatic failure has been reported for nilutamide, with fatal outcome.[6][40][41][42] Similarly to flutamide, nilutamide exhibits mitochondrial toxicity in hepatocytes by inhibiting respiratory complex I (NADH ubiquinone oxidoreductase) (though not respiratory complexes II, III, or IV) in the electron transport chain, resulting in reduced ATP and glutathione production and thus decreased hepatocyte survival.[42][43][44] The nitro group of nilutamide has been theorized to be involved in both its hepatotoxicity and its pulmonary toxicity.[44][45]

Pharmacology

Antiandrogen

Nilutamide acts as a selective competitive silent antagonist of the androgen receptor (AR) (IC50 = 412 nM),[46] which prevents testosterone and other androgens from activating the AR.[13] The affinity of nilutamide for the AR is 100-fold less than that of testosterone, thus necessitating the use of relatively high dosages to achieve significant effectiveness.[47] Nilutamide has approximately the same affinity for the AR as 2-hydroxyflutamide.[48] Similarly to 2-hydroxyflutamide, but unlike bicalutamide, nilutamide is able to weakly activate the AR at high concentrations.[48]

Like other NSAAs such as flutamide and bicalutamide, nilutamide, without concomitant GnRH analogue therapy, increases serum androgen (by two-fold in the case of testosterone), estrogen, and prolactin levels due to inhibition of AR-mediated suppression of steroidogenesis via negative feedback on the hypothalamic-pituitary-gonadal axis.[13] As such, though nilutamide is still effective as an antiandrogen as a monotherapy, it is given in combination with a GnRH analogue such as leuprorelin in prostate cancer to suppress androgen concentrations to castrate levels in order to attain maximal androgen blockade (MAB).[13]

Like flutamide and bicalutamide, nilutamide is able to cross the blood-brain-barrier and has central antiandrogen actions.[49]

Cytochrome P450 inhibitor

Nilutamide is known to inhibit several cytochrome P450 enzymes, including CYP1A2, CYP2C9, and CYP3A4, and can result in increased levels of medications that are metabolized by these enzymes.[50] It has also been found to inhibit the enzyme CYP17A1 (17α-hydroxylase/17,20-lyase) in vitro and thus the biosynthesis of androgens.[51][52] However, nilutamide monotherapy significantly increases testosterone levels in vivo, so the clinical significance of this finding is uncertain.[51][52]

Pharmacokinetics

Nilutamide has a half-life of 23–87 hours, with a mean of 56 hours,[6] or about two days; this allows for once-daily administration.[9] Steady state (plateau) levels of the drug are attained after two weeks of administration with a dosage of 150 mg twice daily (300 mg/day total).[53] It is metabolized by CYP2C19, with at least five metabolites.[5] Virtually all of the antiandrogenic activity of nilutamide comes from the parent drug (as opposed to metabolites).[54]

References

  1. ↑ https://livertox.nlm.nih.gov/Nilutamide.htm
  2. ↑ https://www.drugs.com/pregnancy/nilutamide.html
  3. 1 2 3 4 Michael C. Perry; Donald C. Doll; Carl E. Freter (30 July 2012). Perry's The Chemotherapy Source Book. Lippincott Williams & Wilkins. pp. 711–. ISBN 978-1-4698-0343-2.
  4. 1 2 3 4 Thomas L. Lemke; David A. Williams (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1373–. ISBN 978-1-60913-345-0.
  5. 1 2 Bruce A. Chabner; Dan L. Longo (8 November 2010). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 680–. ISBN 978-1-60547-431-1.
  6. 1 2 3 4 5 JORDAN V. CRAIG; B.J.A. Furr (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 347,350,356. ISBN 978-1-59259-152-7. Although the t1/2 of nilutamide is h (mean 56 h) (39), suggesting that once-daily dosing would be appropriate, a three times per day regimen has been employed in most clinical trials.
  7. 1 2 C.R. Ganellin; David J. Triggle (21 November 1996). Dictionary of Pharmacological Agents. CRC Press. pp. 1431–. ISBN 978-0-412-46630-4.
  8. ↑ Dr. Ian Morton; I.K. Morton; Judith M. Hall (31 October 1999). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 199–. ISBN 978-0-7514-0499-9.
  9. 1 2 3 4 5 Louis J Denis; Keith Griffiths; Amir V Kaisary; Gerald P Murphy (1 March 1999). Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment. CRC Press. pp. 280–. ISBN 978-1-85317-422-3. Cite uses deprecated parameter |coauthors= (help)
  10. ↑ Wellington K, Keam SJ (2006). "Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer". Drugs. 66 (6): 837–50. doi:10.2165/00003495-200666060-00007. PMID 16706554.
  11. ↑ Edward J. Pavlik (6 December 2012). Estrogens, Progestins, and Their Antagonists: Health Issues. Springer Science & Business Media. pp. 167–. ISBN 978-1-4612-4096-9.
  12. ↑ Bohl, C. E.; Gao, W.; Miller, D. D.; Bell, C. E.; Dalton, J. T. (2005). "Structural basis for antagonism and resistance of bicalutamide in prostate cancer". Proceedings of the National Academy of Sciences. 102 (17): 6201–6206. doi:10.1073/pnas.0500381102. ISSN 0027-8424.
  13. 1 2 3 4 5 Louis Denis (6 December 2012). Antiandrogens in Prostate Cancer: A Key to Tailored Endocrine Treatment. Springer Science & Business Media. pp. 194–210. ISBN 978-3-642-45745-6.
  14. ↑ Michael Boarder; David Newby; Phyllis Navti (25 March 2010). Pharmacology for Pharmacy and the Health Sciences: A Patient-centred Approach. OUP Oxford. pp. 632–. ISBN 978-0-19-955982-4.
  15. ↑ Vincent T. DeVita; Theodore S. Lawrence; Steven A. Rosenberg (18 March 2016). Prostate and Other Genitourinary Cancers: Cancer: Principles & Practice of Oncology. Wolters Kluwer Health. pp. 1006–. ISBN 978-1-4963-5421-1.
  16. 1 2 3 4 Chawnshang Chang (1 January 2005). Prostate Cancer: Basic Mechanisms and Therapeutic Approaches. World Scientific. pp. 11–. ISBN 978-981-256-920-2.
  17. 1 2 James Leonard Gulley (2011). Prostate Cancer. Demos Medical Publishing. pp. 81–. ISBN 978-1-935281-91-7.
  18. ↑ Jonathan Upfal (2006). The Australian Drug Guide: Every Person's Guide to Prescription and Over-the-counter Medicines, Street Drugs, Vaccines, Vitamins and Minerals... Black Inc. pp. 283–. ISBN 978-1-86395-174-6.
  19. 1 2 Baudewijntje P.C. Kreukels; Thomas D. Steensma; Annelou L.C. de Vries (1 July 2013). Gender Dysphoria and Disorders of Sex Development: Progress in Care and Knowledge. Springer Science & Business Media. pp. 280–. ISBN 978-1-4614-7441-8.
  20. 1 2 3 4 5 Asscheman, H.; Gooren, I. J. G.; Peereboom-Wynia, J. D. R. (1989). "Reduction in undesired sexual hair growth with Anandron in male-to-female transsexuals-experiences with a novel androgen receptor blocker". Clinical and Experimental Dermatology. 14 (5): 361–363. doi:10.1111/j.1365-2230.1989.tb02585.x. ISSN 0307-6938.
  21. 1 2 3 4 5 6 7 8 9 Rao, B.Ramanath; de Voogt, H.J.; Geldof, A.A.; Gooren, L.J.G.; Bouman, F.G. (1988). "Merits and considerations in the use of anti-androgen". Journal of Steroid Biochemistry. 31 (4): 731–737. doi:10.1016/0022-4731(88)90024-6. ISSN 0022-4731.
  22. 1 2 3 4 van Kemenade, Johannes F. L. M.; Cohen-Kettenis, Peggy T.; Cohen, Leo; Gooren, Louis J. G. (1989). "Effects of the pure antiandrogen RU 23.903 (anandron) on sexuality, aggression, and mood in male-to-female transsexuals". Archives of Sexual Behavior. 18 (3): 217–228. doi:10.1007/BF01543196. ISSN 0004-0002.
  23. 1 2 3 4 5 6 Gooren, L.; Spinder, T.; Spijkstra, J. J.; Van Kessel, H.; Smals, A.; Rao, B. R.; Hoogslag, M. (1987). "Sex Steroids and Pulsatile Luteinizing Hormone Release in Men. Studies in Estrogen-Treated Agonadal Subjects and Eugonadal Subjects Treated with a Novel Nonsteroidal Antiandrogen". The Journal of Clinical Endocrinology & Metabolism. 64 (4): 763–770. doi:10.1210/jcem-64-4-763. ISSN 0021-972X.
  24. 1 2 3 De Voogt, H. J.; Rao, B. R.; Geldof, A. A.; Gooren, L. J. G.; Bouman, F. G. (1987). "Androgen action blockade does not result in reduction in size but changes histology of the normal human prostate". The Prostate. 11 (4): 305–311. doi:10.1002/pros.2990110403. ISSN 0270-4137.
  25. ↑ Cohen-Kettenis, Peggy T.; Gooren, Louis J.G. (1993). "The Influence of Hormone Treatment on Psychological Functioning of Transsexuals". Journal of Psychology & Human Sexuality. 5 (4): 55–67. doi:10.1300/J056v05n04_04. ISSN 0890-7064.
  26. 1 2 Richard C. Dart (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 521–. ISBN 978-0-7817-2845-4.
  27. ↑ Lisa M DeAngelis MD; Jerome B Posner MD (12 September 2008). Neurologic Complications of Cancer. Oxford University Press, USA. pp. 479–. ISBN 978-0-19-971055-3.
  28. 1 2 Richard A. Lehne (2013). Pharmacology for Nursing Care. Elsevier Health Sciences. pp. 1297–. ISBN 1-4377-3582-7.
  29. ↑ Kenneth L. Becker (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1196–. ISBN 978-0-7817-1750-2.
  30. ↑ Phillipe Camus; Edward C Rosenow III (29 October 2010). Drug-induced and Iatrogenic Respiratory Disease. CRC Press. pp. 235–. ISBN 978-1-4441-2869-7.
  31. ↑ Jeanne Held-Warmkessel (2006). Contemporary Issues in Prostate Cancer: A Nursing Perspective. Jones & Bartlett Learning. pp. 257–. ISBN 978-0-7637-3075-8.
  32. ↑ Alan J. Wein; Louis R. Kavoussi; Andrew C. Novick; Alan W. Partin, Craig A. Peters (25 August 2011). Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. pp. 2939–. ISBN 978-1-4160-6911-9. Cite uses deprecated parameter |coauthors= (help)
  33. ↑ J. Ramon; L.J. Denis (5 June 2007). Prostate Cancer. Springer Science & Business Media. pp. 229–. ISBN 978-3-540-40901-4.
  34. ↑ Mahler, Charles (1996). "A Review of the Clinical Studies with Nilutamide": 105–111. doi:10.1007/978-3-642-45745-6_10. Akaza had to prematurely terminate a nilutamide study in Japan as 12.6% of his patients developed interstitial lung disease [4]. This complication has been mainly observed in Japan and much less in other trials worldwide.
  35. ↑ Micromedex (1 January 2003). USP DI 2003: Drug Information for Healthcare Professionals. Thomson Micromedex. pp. 220–224. ISBN 978-1-56363-429-1.
  36. ↑ Gomez JL, Dupont A, Cusan L, Tremblay M, Tremblay M, Labrie F (1992). "Simultaneous liver and lung toxicity related to the nonsteroidal antiandrogen nilutamide (Anandron): a case report". Am. J. Med. 92 (5): 563–6. PMID 1580304.
  37. ↑ Virgil Craig Jordan; B. J. A. Furr (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 356–. ISBN 978-1-59259-152-7.
  38. ↑ Jeffrey K. Aronson (21 February 2009). Meyler's Side Effects of Endocrine and Metabolic Drugs. Elsevier. pp. 150–. ISBN 978-0-08-093292-7.
  39. ↑ Jafri, Syed-Mohammed R. (2014). "Bicalutamide-induced hepatotoxicity: A rare adverse effect". American Journal of Case Reports. 15: 266–270. doi:10.12659/AJCR.890679. ISSN 1941-5923.
  40. ↑ J. K. Aronson (2011). Side Effects of Drugs Annual: A Worldwide Yearly Survey of New Data in Adverse Drug Reactions. Elsevier. pp. 874–. ISBN 978-0-444-53741-6.
  41. ↑ Marty F, Godart D, Doermann F, Mérillon H (1996). "[Fatal fulminating hepatitis caused by nilutamide. A new case]". Gastroenterol. Clin. Biol. (in French). 20 (8-9): 710–1. PMID 8977826.
  42. 1 2 Merwat, Shehzad N.; Kabbani, Wareef; Adler, Douglas G. (2008). "Fulminant Hepatic Failure due to Nilutamide Hepatotoxicity". Digestive Diseases and Sciences. 54 (4): 910–913. doi:10.1007/s10620-008-0406-8. ISSN 0163-2116. In addition, nilutamide is noted to exhibit mitochondrial toxicity by inhibiting complex I activity of the mitochondrial respiratory chain leading to the impairment of ATP formation and the biosynthesis of glutathione, thereby possibly predisposing the liver to toxicity [13].
  43. ↑ Berson A, Schmets L, Fisch C, Fau D, Wolf C, Fromenty B, Deschamps D, Pessayre D (1994). "Inhibition by nilutamide of the mitochondrial respiratory chain and ATP formation. Possible contribution to the adverse effects of this antiandrogen". J. Pharmacol. Exp. Ther. 270 (1): 167–76. PMID 8035313.
  44. 1 2 Coe, Kevin J.; Jia, Yankai; Ho, Han Kiat; Rademacher, Peter; Bammler, Theo K.; Beyer, Richard P.; Farin, Frederico M.; Woodke, Libby; Plymate, Stephen R.; Fausto, Nelson; Nelson, Sidney D. (2007). "Comparison of the Cytotoxicity of the Nitroaromatic Drug Flutamide to Its Cyano Analogue in the Hepatocyte Cell Line TAMH: Evidence for Complex I Inhibition and Mitochondrial Dysfunction Using Toxicogenomic Screening". Chemical Research in Toxicology. 20 (9): 1277–1290. doi:10.1021/tx7001349. ISSN 0893-228X.
  45. ↑ Boelsterli, Urs; Ho, Han; Zhou, Shufeng; Yeow Leow, Koon (2006). "Bioactivation and Hepatotoxicity of Nitroaromatic Drugs". Current Drug Metabolism. 7 (7): 715–727. doi:10.2174/138920006778520606. ISSN 1389-2002.
  46. ↑ Singh, Shankar; Gauthier, Sylvain; Labrie, Fernand (2000). "Androgen Receptor Antagonists (Antiandrogens) Structure-Activity Relationships". Current Medicinal Chemistry. 7 (2): 211–247. doi:10.2174/0929867003375371. ISSN 0929-8673.
  47. ↑ H.J.T. Coelingh Benni; H.M. Vemer (15 December 1990). Chronic Hyperandrogenic Anovulation. CRC Press. pp. 153–. ISBN 978-1-85070-322-8.
  48. 1 2 William Figg; Cindy H. Chau; Eric J. Small (14 September 2010). Drug Management of Prostate Cancer. Springer Science & Business Media. pp. 71–. ISBN 978-1-60327-829-4.
  49. ↑ Raynaud, Jean-Pierre; Bonne, Claude; Bouton, Marie-Madeleine; Lagace, Lisette; Labrie, Fernand (1979). "Action of a non-steroid anti-androgen, RU 23908, in peripheral and central tissues". Journal of Steroid Biochemistry. 11 (1): 93–99. doi:10.1016/0022-4731(79)90281-4. ISSN 0022-4731.
  50. ↑ Stephen J. Ferrando; James L. Levenson; James A. Owen (20 May 2010). Clinical Manual of Psychopharmacology in the Medically Ill. American Psychiatric Pub. pp. 256–. ISBN 978-1-58562-942-8.
  51. 1 2 Harris, Martin G.; Coleman, Stephen G.; Faulds, Diana; Chrisp, Paul (1993). "Nilutamide". Drugs & Aging. 3 (1): 9–25. doi:10.2165/00002512-199303010-00002. ISSN 1170-229X.
  52. 1 2 Ayub M, Levell MJ (1987). "Inhibition of rat testicular 17 alpha-hydroxylase and 17,20-lyase activities by anti-androgens (flutamide, hydroxyflutamide, RU23908, cyproterone acetate) in vitro". J. Steroid Biochem. 28 (1): 43–7. doi:10.1016/0022-4731(87)90122-1. PMID 2956461.
  53. ↑ Louis Denis (6 December 2012). Antiandrogens in Prostate Cancer: A Key to Tailored Endocrine Treatment. Springer Science & Business Media. pp. 202–. ISBN 978-3-642-45745-6. The plateau level of nilutamide (steady state) was obtained after about 14 days of repeated administration of the drug (150 mg b.i.d.) and did not depend upon intervals between doses.
  54. ↑ Mahler, Ch; Verhelst, J; Denis, L (1998). "Clinical Pharmacokinetics of the Antiandrogens and Their Efficacy in Prostate Cancer". Clinical Pharmacokinetics. 34 (5): 405–417. doi:10.2165/00003088-199834050-00005. ISSN 0312-5963.
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