nilutamide

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.{{cite book| vauthors = Upfal J |title=The Australian Drug Guide: Every Person's Guide to Prescription and Over-the-counter Medicines, Street Drugs, Vaccines, Vitamins and Minerals...|url=https://books.google.com/books?id=7O9kiqN2q2YC&pg=PA283|year=2006|publisher=Black Inc.|isbn=978-1-86395-174-6|pages=283–}} It is not indicated as a monotherapy in prostate cancer. Only one small non-comparative study has assessed nilutamide as a monotherapy in prostate cancer.{{cite journal | vauthors = Anderson J | title = The role of antiandrogen monotherapy in the treatment of prostate cancer | journal = BJU International | volume = 91 | issue = 5 | pages = 455–461 | date = March 2003 | pmid = 12603397 | doi = 10.1046/j.1464-410X.2003.04026.x | quote = Trial experience with nilutamide monotherapy is limited to one small non-comparative study involving 26 patients with metastatic disease given nilutamide 100 mg three times daily (the dose used when nilutamide is administered as a component of MAB) [14]. The median progression-free survival in these patients was 9 months, with a median overall survival of 23 months. There have been no comparative trials of nilutamide with other antiandrogens or with castration [15]. The limited available data on nilutamide monotherapy means that no meaningful conclusions about the role of nilutamide in this setting can be determined. Nilutamide is not licensed as monotherapy. | s2cid = 8639102 | doi-access = }}

Nilutamide has been used to prevent the effects of the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer.{{cite journal | vauthors = Thompson IM | title = Flare Associated with LHRH-Agonist Therapy | journal = Reviews in Urology | volume = 3 | issue = Suppl 3 | pages = S10–S14 | date = 2001 | pmid = 16986003 | pmc = 1476081 }}{{cite journal | vauthors = Scaletscky R, Smith JA | title = Disease flare with gonadotrophin-releasing hormone (GnRH) analogues. How serious is it? | journal = Drug Safety | volume = 8 | issue = 4 | pages = 265–270 | date = April 1993 | pmid = 8481213 | doi = 10.2165/00002018-199308040-00001 | s2cid = 36964191 }}{{cite journal | vauthors = Kuhn JM, Billebaud T, Navratil H, Moulonguet A, Fiet J, Grise P, Louis JF, Costa P, Husson JM, Dahan R | display-authors = 6 | title = Prevention of the transient adverse effects of a gonadotropin-releasing hormone analogue (buserelin) in metastatic prostatic carcinoma by administration of an antiandrogen (nilutamide) | journal = The New England Journal of Medicine | volume = 321 | issue = 7 | pages = 413–418 | date = August 1989 | pmid = 2503723 | doi = 10.1056/NEJM198908173210701 }}

Nilutamide has been studied for use as a component of feminizing hormone therapy for transgender women.{{cite book| vauthors = Kreukels BP, Steensma TD, De Vries AL |title= Gender Dysphoria and Disorders of Sex Development: Progress in Care and Knowledge|url=https://books.google.com/books?id=YQ5GAAAAQBAJ&pg=PA280|date=1 July 2013|publisher=Springer Science & Business Media|isbn=978-1-4614-7441-8|pages=280–}} It has been assessed in at least five small clinical studies for this purpose in treatment-naive subjects.{{cite journal | vauthors = Asscheman H, Gooren LJ, Peereboom-Wynia JD | title = Reduction in undesired sexual hair growth with anandron in male-to-female transsexuals--experiences with a novel androgen receptor blocker | journal = Clinical and Experimental Dermatology | volume = 14 | issue = 5 | pages = 361–363 | date = September 1989 | pmid = 2612040 | doi = 10.1111/j.1365-2230.1989.tb02585.x | s2cid = 45303518 }}{{cite journal | vauthors = Rao BR, de Voogt HJ, Geldof AA, Gooren LJ, Bouman FG | title = Merits and considerations in the use of anti-androgen | journal = Journal of Steroid Biochemistry | volume = 31 | issue = 4B | pages = 731–737 | date = October 1988 | pmid = 3143862 | doi = 10.1016/0022-4731(88)90024-6 }}{{cite journal | vauthors = van Kemenade JF, Cohen-Kettenis PT, Cohen L, Gooren LJ | title = Effects of the pure antiandrogen RU 23.903 (anandron) on sexuality, aggression, and mood in male-to-female transsexuals | journal = Archives of Sexual Behavior | volume = 18 | issue = 3 | pages = 217–228 | date = June 1989 | pmid = 2751416 | doi = 10.1007/BF01543196 | s2cid = 44664956 }}{{cite journal | vauthors = Gooren L, Spinder T, Spijkstra JJ, van Kessel H, Smals A, Rao BR, Hoogslag M | title = Sex steroids and pulsatile luteinizing hormone release in men. Studies in estrogen-treated agonadal subjects and eugonadal subjects treated with a novel nonsteroidal antiandrogen | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 64 | issue = 4 | pages = 763–770 | date = April 1987 | pmid = 3102546 | doi = 10.1210/jcem-64-4-763 }}{{cite journal | vauthors = de Voogt HJ, Rao BR, Geldof AA, Gooren LJ, Bouman FG | title = Androgen action blockade does not result in reduction in size but changes histology of the normal human prostate | journal = The Prostate | volume = 11 | issue = 4 | pages = 305–311 | year = 1987 | pmid = 2960959 | doi = 10.1002/pros.2990110403 | s2cid = 84632739 }} 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, including breast development, decreased body hair (though not facial hair), decreased morning erections and sex drive, and positive psychological and emotional changes.{{cite journal| vauthors = Cohen-Kettenis PT, Gooren LJ |title=The Influence of Hormone Treatment on Psychological Functioning of Transsexuals|journal=Journal of Psychology & Human Sexuality|volume=5|issue=4|year=1993|pages=55–67|issn=0890-7064|doi=10.1300/J056v05n04_04|s2cid=145237890 }} Signs of breast development occurred in all subjects within 6 weeks and were associated with increased nipple sensitivity, and along with decreased hair growth, were the earliest sign of feminization.

Nilutamide did not change the size of the prostate gland (which is the same as with high-dosage cyproterone acetate and ethinylestradiol 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.{{cite book|title=Drugs & Aging|url=https://books.google.com/books?id=roFNAQAAIAAJ|year=1993|publisher=Adis International|quote=In 16 male subjects undergoing androgen blockade with nilutamide 100 to 300 mg/day for 8 weeks for male to female gender reassignment, prostate volume was not changed (de Voogt et al. 1987).|access-date=2 April 2018|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110224014/https://books.google.com/books?id=roFNAQAAIAAJ|url-status=live}} In addition, readily apparent histological changes were observed in the testes, including a reduction in tubular and interstitial cells.

Nilutamide was found to more than double luteinizing hormone (LH) and testosterone levels and to triple estradiol levels. In contrast, follicle-stimulating hormone levels remained unchanged. A slight but significant increase in prolactin levels was observed, and levels of sex hormone-binding globulin increased as well. The addition of ethinylestradiol to nilutamide therapy after 8 weeks abolished the increase in LH, testosterone, and estradiol levels and dramatically suppressed testosterone levels, into the castrate range. 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.

Nilutamide has been assessed in the treatment of acne and seborrhea in women in at least one small clinical study.{{cite journal | vauthors = Couzinet B, Thomas G, Thalabard JC, Brailly S, Schaison G | title = Effects of a pure antiandrogen on gonadotropin secretion in normal women and in polycystic ovarian disease | journal = Fertility and Sterility | volume = 52 | issue = 1 | pages = 42–50 | date = July 1989 | pmid = 2744186 | doi = 10.1016/s0015-0282(16)60786-0 | doi-access = }}{{cite journal | vauthors = Namer M | title = Clinical applications of antiandrogens | journal = Journal of Steroid Biochemistry | volume = 31 | issue = 4B | pages = 719–729 | date = October 1988 | pmid = 2462132 | doi = 10.1016/0022-4731(88)90023-4 }} The dosage used was 200 mg/day, and in the study, "seborrhea and acne decreased markedly within the first month and practically disappeared after 2 months of [nilutamide] treatment."

Nilutamide is available in the form of 50 and 150 mg oral tablets.{{cite book|vauthors=Meyers RA|title=Translational Medicine: Molecular Pharmacology and Drug Discovery|url=https://books.google.com/books?id=kuhPDwAAQBAJ&pg=PA46|date=2 March 2018|publisher=Wiley|isbn=978-3-527-68719-0|pages=46–|access-date=2 August 2018|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110224026/https://books.google.com/books?id=kuhPDwAAQBAJ&pg=PA46|url-status=live}}

General side effects of NSAAs, including nilutamide, include gynecomastia, 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.{{cite book| vauthors = Dart RC |title=Medical Toxicology|url=https://books.google.com/books?id=BfdighlyGiwC&pg=PA521|year=2004|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-2845-4|pages=521–}}{{cite book|vauthors=DeAngelis LM, Posner JB|title=Neurologic Complications of Cancer|url=https://books.google.com/books?id=mpZ8Dp2KdHMC&pg=PA479|date=12 September 2008|publisher=Oxford University Press, USA|isbn=978-0-19-971055-3|pages=479–|access-date=21 February 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110224047/https://books.google.com/books?id=mpZ8Dp2KdHMC&pg=PA479|url-status=live}}{{cite book|vauthors=Lehne RA|title=Pharmacology for Nursing Care|url=https://books.google.com/books?id=_4SwO2dHcAIC&pg=PA1297|year=2013|publisher=Elsevier Health Sciences|isbn=978-1-4377-3582-6|pages=1297–|access-date=12 October 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110224019/https://books.google.com/books?id=_4SwO2dHcAIC&pg=PA1297|url-status=live}} Also, nausea (24–27%), vomiting, constipation (20%), and insomnia (16%) may occur with nilutamide. Nilutamide monotherapy is known to eventually induce gynecomastia in 40 to 80% of men treated with it for prostate cancer, usually within 6 to 9 months of treatment initiation.{{cite journal | vauthors = Bautista-Vidal C, Barnoiu O, García-Galisteo E, Gómez-Lechuga P, Baena-González V | title = Treatment of gynecomastia in patients with prostate cancer and androgen deprivation | journal = Actas Urologicas Espanolas | volume = 38 | issue = 1 | pages = 34–40 | year = 2014 | pmid = 23850393 | doi = 10.1016/j.acuroe.2013.10.002 | quote = [...] the frequency of gynecomastia with antiandrogens in monotherapy is [...] around [...] 79% with nilutamide [...] }}{{cite journal | vauthors = Deepinder F, Braunstein GD | title = Drug-induced gynecomastia: an evidence-based review | journal = Expert Opinion on Drug Safety | volume = 11 | issue = 5 | pages = 779–795 | date = September 2012 | pmid = 22862307 | doi = 10.1517/14740338.2012.712109 | quote = Treatment with estrogen has the highest incidence of gynecomastia, at 40 – 80%, anti-androgens, including flutamide, bicalutamide and nilutamide, are next, with a 40 – 70% incidence, followed by GnRH analogs (goserelin, leuprorelin) and combined androgen deprivation [...] | s2cid = 22938364 }}{{cite journal | vauthors = Michalopoulos NV, Keshtgar MR | title = Images in clinical medicine. Gynecomastia induced by prostate-cancer treatment | journal = The New England Journal of Medicine | volume = 367 | issue = 15 | pages = 1449 | date = October 2012 | pmid = 23050528 | doi = 10.1056/NEJMicm1209166 | quote = Gynecomastia occurs in up to 80% of patients who receive nonsteroidal antiandrogens (eg, bicalutamide, flutamide, or nilutamide), usually within the first 6 to 9 months after the initiation of treatment. }}{{cite journal | vauthors = Di Lorenzo G, Autorino R, Perdonà S, De Placido S | title = Management of gynaecomastia in patients with prostate cancer: a systematic review | journal = The Lancet. Oncology | volume = 6 | issue = 12 | pages = 972–979 | date = December 2005 | pmid = 16321765 | doi = 10.1016/S1470-2045(05)70464-2 }}

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,{{cite book|vauthors=Becker KL|title=Principles and Practice of Endocrinology and Metabolism|url=https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1196|year=2001|publisher=Lippincott Williams & Wilkins|isbn=978-0-7817-1750-2|pages=1196–|access-date=12 October 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110085133/https://books.google.com/books?id=FVfzRvaucq8C&pg=PA1196|url-status=live}} a disulfiram-like alcohol intolerance (19%), interstitial pneumonitis (0.77–2.4%){{cite book| vauthors = Gulley JL |title=Prostate Cancer|url=https://books.google.com/books?id=WJkjgbRJe3EC&pg=PT81|year=2011|publisher=Demos Medical Publishing|isbn=978-1-935281-91-7|pages=81–}}{{cite book| vauthors = Camus P, Rosenow III EC |title=Drug-induced and Iatrogenic Respiratory Disease|url=https://books.google.com/books?id=QlJsBgAAQBAJ&pg=PA235|date=29 October 2010|publisher=CRC Press|isbn=978-1-4441-2869-7|pages=235–}}{{cite book| vauthors = Held-Warmkessel J |title=Contemporary Issues in Prostate Cancer: A Nursing Perspective|url=https://books.google.com/books?id=dZe4ZSVDdBsC&pg=PA257|year=2006|publisher=Jones & Bartlett Learning|isbn=978-0-7637-3075-8|pages=257–}} (which can result in dyspnea (1%) as a secondary effect and can progress to pulmonary fibrosis),{{cite book|vauthors=Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA|author-link4=Alan W. Partin|title=Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set|url=https://books.google.com/books?id=fu3BBwAAQBAJ&pg=PA2939|date=25 August 2011|publisher=Elsevier Health Sciences|isbn=978-1-4160-6911-9|pages=2939–|access-date=21 February 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110224041/https://books.google.com/books?id=fu3BBwAAQBAJ&pg=PA2939|url-status=live}} and hepatitis (1%), and has a higher incidence of nausea and vomiting compared to other NSAAs.{{cite book| vauthors = Chang C |title=Prostate Cancer: Basic Mechanisms and Therapeutic Approaches|url=https://books.google.com/books?id=4xQAr3Uh8EUC&pg=PA11|date=1 January 2005|publisher=World Scientific|isbn=978-981-256-920-2|pages=11–}}{{cite book| vauthors = Ramon J, Denis LJ |title=Prostate Cancer|url=https://books.google.com/books?id=Bg6ZbqhhboUC&pg=PA229|date=5 June 2007|publisher=Springer Science & Business Media|isbn=978-3-540-40901-4|pages=229–}} 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.{{cite book| vauthors = Mahler C |title=Antiandrogens in Prostate Cancer|chapter=A Review of the Clinical Studies with Nilutamide|year=1996|pages=105–111|doi=10.1007/978-3-642-45745-6_10|quote=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.|isbn=978-3-642-45747-0}}{{cite book|author=Micromedex|title=USP DI 2003: Drug Information for Healthcare Professionals|url=https://books.google.com/books?id=zEzWtsVl-KgC|date=1 January 2003|publisher=Thomson Micromedex|isbn=978-1-56363-429-1|pages=220–224|access-date=12 October 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110224310/https://books.google.com/books?id=zEzWtsVl-KgC|url-status=live}} There is a case report of simultaneous liver and lung toxicity in a nilutamide-treated patient.{{cite journal | vauthors = Gomez JL, Dupont A, Cusan L, Tremblay M, Tremblay M, Labrie F | title = Simultaneous liver and lung toxicity related to the nonsteroidal antiandrogen nilutamide (Anandron): a case report | journal = The American Journal of Medicine | volume = 92 | issue = 5 | pages = 563–566 | date = May 1992 | pmid = 1580304 | doi = 10.1016/0002-9343(92)90756-2 }}

There is also a risk of hepatotoxicity with nilutamide, though occurrence is very rare and the risk is significantly less than with flutamide.{{cite book| vauthors = Aronson JK |title=Meyler's Side Effects of Endocrine and Metabolic Drugs|url=https://books.google.com/books?id=BWMeSwVwfTkC&pg=PA150|date=21 February 2009|publisher=Elsevier|isbn=978-0-08-093292-7|pages=150–}} The incidence of abnormal liver function tests (e.g., elevated liver enzymes) has been variously reported as 2 to 33% with nilutamide. For comparison, the risk of elevated liver enzymes has been reported as 4 to 62% in the case of flutamide.{{cite journal | vauthors = McLeod DG | title = Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer | journal = The Oncologist | volume = 2 | issue = 1 | pages = 18–27 | date = 1997 | pmid = 10388026 | doi = 10.1634/theoncologist.2-1-18 | quote = Incidences of abnormal liver function test results have been variously reported from 2%-33% in nilutamide groups [13, 32, 33, 45] and from 4%-62% in flutamide groups [5, 7, 9, 11, 34, 38-40, 48] in trials of monotherapy and CAB. | doi-access = free }}{{cite journal | vauthors = Hussain S, Haidar A, Bloom RE, Zayouna N, Piper MH, Jafri SM | title = Bicalutamide-induced hepatotoxicity: A rare adverse effect | journal = The American Journal of Case Reports | volume = 15 | pages = 266–270 | year = 2014 | pmid = 24967002 | pmc = 4068966 | doi = 10.12659/AJCR.890679 }} The risk of hepatotoxicity with nilutamide has been described as far less than with flutamide.{{cite web | url = https://livertox.nih.gov/Nilutamide.htm | title = Nilutamide - LiverTox | website = National Institutes of Health | date = 2012 | pmid = 31643176 | access-date = 24 September 2018 | quote = In large registration clinical trials, ALT elevations occurred in 2% to 33% of patients during nilutamide therapy. The elevations were usually mild, asymptomatic and transient, rarely requiring drug discontinuation. In rare instances, clinically apparent acute liver injury has occurred during nilutamide therapy, but the number of published cases are few, and the agent appears to be far less hepatotoxic than flutamide. | archive-date = 24 September 2018 | archive-url = https://web.archive.org/web/20180924224717/https://livertox.nih.gov/Nilutamide.htm | url-status = live }} Fulminant hepatic failure has been reported for nilutamide, with fatal outcome.{{cite book| vauthors = Aronson JK |title=Side Effects of Drugs Annual: A Worldwide Yearly Survey of New Data in Adverse Drug Reactions|url=https://books.google.com/books?id=zegpAgEt3CcC&pg=PA874|year=2011|publisher=Elsevier|isbn=978-0-444-53741-6|pages=874–}}{{cite journal | vauthors = Marty F, Godart D, Doermann F, Mérillon H | title = [Fatal fulminating hepatitis caused by nilutamide. A new case] | language = fr | journal = Gastroenterologie Clinique et Biologique | volume = 20 | issue = 8–9 | pages = 710–711 | year = 1996 | pmid = 8977826 }}{{cite journal | vauthors = Merwat SN, Kabbani W, Adler DG | title = Fulminant hepatic failure due to nilutamide hepatotoxicity | journal = Digestive Diseases and Sciences | volume = 54 | issue = 4 | pages = 910–913 | date = April 2009 | pmid = 18688719 | doi = 10.1007/s10620-008-0406-8 | quote = 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]. | s2cid = 27421870 }} Between 1986 and 2003, the numbers of published cases of hepatotoxicity for antiandrogens totaled 46 for flutamide, 21 for cyproterone acetate, 4 for nilutamide, and 1 for bicalutamide.{{cite book| vauthors = Chitturi S, Farrell GC |title=Drug-Induced Liver Disease|chapter=Adverse Effects of Hormones and Hormone Antagonists on the Liver|journal=Current Treatment Options in Gastroenterology|year=2013|volume=3|issue=6|pages=605–619|publisher=Academic Press |doi=10.1016/B978-0-12-387817-5.00033-9|pmid=11096606|quote=Liver injury is well recognized with all antiandrogens (Table 33-3). Thus, among all published cases identified between 1986 and 2003, flutamide (46), cyproterone (21), nilutamide (4), and bicalutamide (1) were implicated [107,108].|isbn=9780123878175}} 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.{{cite journal | vauthors = Berson A, Schmets L, Fisch C, Fau D, Wolf C, Fromenty B, Deschamps D, Pessayre D | display-authors = 6 | title = Inhibition by nilutamide of the mitochondrial respiratory chain and ATP formation. Possible contribution to the adverse effects of this antiandrogen | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 270 | issue = 1 | pages = 167–176 | date = July 1994 | doi = 10.1016/S0022-3565(25)22351-5 | pmid = 8035313 }}{{cite journal | vauthors = Coe KJ, Jia Y, Ho HK, Rademacher P, Bammler TK, Beyer RP, Farin FM, Woodke L, Plymate SR, Fausto N, Nelson SD | display-authors = 6 | title = 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 | journal = Chemical Research in Toxicology | volume = 20 | issue = 9 | pages = 1277–1290 | date = September 2007 | pmid = 17702527 | pmc = 2802183 | doi = 10.1021/tx7001349 }} The nitro group of nilutamide has been theorized to be involved in both its hepatotoxicity and its pulmonary toxicity.{{cite journal | vauthors = Boelsterli UA, Ho HK, Zhou S, Leow KY | title = Bioactivation and hepatotoxicity of nitroaromatic drugs | journal = Current Drug Metabolism | volume = 7 | issue = 7 | pages = 715–727 | date = October 2006 | pmid = 17073576 | doi = 10.2174/138920006778520606 }}

{{Side effects of combined androgen blockade with nilutamide and surgical castration}}

{{Side effects of combined androgen blockade with nilutamide and a GnRH agonist}}

{{Affinities of selected androgen receptor ligands}}

Nilutamide acts as a selective competitive silent antagonist of the AR (IC₅₀ = 412 nM),{{cite journal | vauthors = Singh SM, Gauthier S, Labrie F | title = Androgen receptor antagonists (antiandrogens): structure-activity relationships | journal = Current Medicinal Chemistry | volume = 7 | issue = 2 | pages = 211–247 | date = February 2000 | pmid = 10637363 | doi = 10.2174/0929867003375371 }} which prevents androgens like testosterone and DHT from activating the receptor.{{cite book| vauthors = Denis L |title=Antiandrogens in Prostate Cancer: A Key to Tailored Endocrine Treatment|url=https://books.google.com/books?id=jqZDBQAAQBAJ&pg=PT194|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-45745-6|pages=194–210}} The affinity of nilutamide for the AR is about 1 to 4% of that of testosterone and is similar to that of bicalutamide and 2-hydroxyflutamide.{{cite book| vauthors = Gaillard M |title=Antiandrogens in Prostate Cancer|chapter=Pharmacodynamics and Pharmacokinetics of Nilutamide in Animal and Man|year=1996|pages=95–103|doi=10.1007/978-3-642-45745-6_9|isbn=978-3-642-45747-0}}{{cite book|vauthors=Figg W, Chau CH, Small EJ|title=Drug Management of Prostate Cancer|url=https://books.google.com/books?id=4KDrjeWA5-UC&pg=PA71|date=14 September 2010|publisher=Springer Science & Business Media|isbn=978-1-60327-829-4|pages=71–|access-date=12 October 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110224030/https://books.google.com/books?id=4KDrjeWA5-UC&pg=PA71|url-status=live}}{{cite book| vauthors = Benni HJ, Vemer HM |title=Chronic Hyperandrogenic Anovulation|url=https://books.google.com/books?id=q6zqFrCLUoIC&pg=PA153|date=15 December 1990|publisher=CRC Press|isbn=978-1-85070-322-8|pages=153–}} Similarly to 2-hydroxyflutamide, but unlike bicalutamide, nilutamide is able to weakly activate the AR at high concentrations. It does not inhibit 5α-reductase.{{cite journal | vauthors = Raynaud JP, Fiet J, Le Goff JM, Martin PM, Moguilewsky M, Ojasoo T | title = Design of antiandrogens and their mechanisms of action: a case study (anandron) | journal = Hormone Research | volume = 28 | issue = 2–4 | pages = 230–241 | year = 1987 | pmid = 3331376 | doi = 10.1159/000180948 }}

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. 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).

Like flutamide and bicalutamide, nilutamide is able to cross the blood–brain barrier and has central antiandrogen actions.{{cite journal | vauthors = Raynaud JP, Bonne C, Bouton MM, Lagace L, Labrie F | title = Action of a non-steroid anti-androgen, RU 23908, in peripheral and central tissues | journal = Journal of Steroid Biochemistry | volume = 11 | issue = 1A | pages = 93–99 | date = July 1979 | pmid = 385986 | doi = 10.1016/0022-4731(79)90281-4 }}

{{Relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor}}

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.{{cite book| vauthors= Ferrando SJ, Levenson JL, Owen JA |title=Clinical Manual of Psychopharmacology in the Medically Ill|url=https://books.google.com/books?id=9b5NkWZ5k8wC&pg=PA256|date=20 May 2010|publisher=American Psychiatric Pub|isbn=978-1-58562-942-8|pages=256–}} It has also been found to inhibit the enzyme CYP17A1 (17α-hydroxylase/17,20-lyase) in vitro and thus the biosynthesis of androgens.{{cite journal | vauthors = Harris MG, Coleman SG, Faulds D, Chrisp P | title = Nilutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer | journal = Drugs & Aging | volume = 3 | issue = 1 | pages = 9–25 | year = 1993 | pmid = 8453188 | doi = 10.2165/00002512-199303010-00002 | s2cid = 262029302 }}{{cite journal | vauthors = Ayub M, Levell MJ | title = Inhibition of rat testicular 17 alpha-hydroxylase and 17,20-lyase activities by anti-androgens (flutamide, hydroxyflutamide, RU23908, cyproterone acetate) in vitro | journal = Journal of Steroid Biochemistry | volume = 28 | issue = 1 | pages = 43–47 | date = July 1987 | pmid = 2956461 | doi = 10.1016/0022-4731(87)90122-1 }} However, nilutamide monotherapy significantly increases testosterone levels in vivo, so the clinical significance of this finding is uncertain.

Nilutamide has an elimination half-life of 23 to 87 hours, with a mean of 56 hours, or about two days; this allows for once-daily administration. 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).{{cite book| vauthors = Denis L |title=Antiandrogens in Prostate Cancer: A Key to Tailored Endocrine Treatment|url=https://books.google.com/books?id=jqZDBQAAQBAJ&pg=PT202|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-3-642-45745-6|pages=202–|quote=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.}} It is metabolized by CYP2C19, with at least five metabolites.{{cite book|vauthors=Chabner BA, Longo DL|title=Cancer Chemotherapy and Biotherapy: Principles and Practice|url=https://books.google.com/books?id=WL4arNFsQa8C&pg=PA680|date=8 November 2010|publisher=Lippincott Williams & Wilkins|isbn=978-1-60547-431-1|pages=680–|access-date=12 October 2016|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110224032/https://books.google.com/books?id=WL4arNFsQa8C&pg=PA680|url-status=live}} Virtually all of the antiandrogenic activity of nilutamide comes from the parent drug (as opposed to metabolites).{{cite journal | vauthors = Mahler C, Verhelst J, Denis L | title = Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer | journal = Clinical Pharmacokinetics | volume = 34 | issue = 5 | pages = 405–417 | date = May 1998 | pmid = 9592622 | doi = 10.2165/00003088-199834050-00005 | s2cid = 25200595 }}

Nilutamide is structurally related to the first-generation NSAAs flutamide and bicalutamide as well as to the second-generation NSAAs enzalutamide and apalutamide.

Nilutamide was developed by Roussel and was first described in 1977.{{cite journal| vauthors = Labrie F, Lagacé L, Ferland L, Kelly PA, Drouin J, Massicotte J, Bonne C, Raynaud JP, Dorrington JH | display-authors = 6 |title=Interactions Between LHRH, Sex Steroids and "Inhibin" in the Control of LH and FSH Secretion|journal=International Journal of Andrology|volume=1|issue=s2a|year=1978|pages=81–101|issn=0105-6263|doi=10.1111/j.1365-2605.1978.tb00008.x|doi-access=free}} It was first introduced for medical use in 1987 in France{{cite book| vauthors = Fischer J, Klein C, Childers WE |title=Successful Drug Discovery|url=https://books.google.com/books?id=t-JVDwAAQBAJ&pg=PA98|date=16 April 2018|publisher=Wiley|isbn=978-3-527-80868-7|pages=98–}} and was the second NSAA to be marketed, with flutamide preceding it and bicalutamide following it in 1995.{{cite journal | vauthors = Wellington K, Keam SJ | title = Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer | journal = Drugs | volume = 66 | issue = 6 | pages = 837–850 | year = 2006 | pmid = 16706554 | doi = 10.2165/00003495-200666060-00007 | s2cid = 46966712 }} It was not introduced until 1996 in the United States.{{cite book| vauthors = Pavlik EJ |title=Estrogens, Progestins, and Their Antagonists: Health Issues|url=https://books.google.com/books?id=LAnpBwAAQBAJ&pg=PA167|date=6 December 2012|publisher=Springer Science & Business Media|isbn=978-1-4612-4096-9|pages=167–}}{{cite journal | vauthors = Bohl CE, Gao W, Miller DD, Bell CE, Dalton JT | title = Structural basis for antagonism and resistance of bicalutamide in prostate cancer | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 102 | issue = 17 | pages = 6201–6206 | date = April 2005 | pmid = 15833816 | pmc = 1087923 | doi = 10.1073/pnas.0500381102 | doi-access = free | bibcode = 2005PNAS..102.6201B }}{{Cite web | url=http://adisinsight.springer.com/drugs/800004379 | title=Nilutamide - AdisInsight | access-date=26 June 2017 | archive-date=5 May 2021 | archive-url=https://web.archive.org/web/20210505173834/https://adisinsight.springer.com/drugs/800004379 | url-status=live }}

Nilutamide is the generic name of the drug and its {{abbrlink|INN|International Nonproprietary Name}}, {{abbrlink|USAN|United States Adopted Name}}, {{abbrlink|BAN|British Approved Name}}, and {{abbrlink|DCF|Dénomination Commune Française}}.

Nilutamide is marketed under the brand name Nilandron in the United States and under the brand name Anandron elsewhere in the world such as in Australia, Canada, Europe, and Latin America.

Nilutamide is or has been available in the United States, Canada, Australia, Europe, Latin America, Egypt, and Lebanon. In Europe, it is or has been available in Belgium, Croatia, the Czech Republic, Finland, France, the Netherlands, Norway, Poland, Portugal, Serbia, Sweden, Switzerland, and Yugoslavia. in Latin America, it is or has been available in Argentina, Brazil, and Mexico.

The combination of an estrogen and nilutamide as a form of combined androgen blockade for the treatment of prostate cancer has been studied in animals.{{cite journal | vauthors = Rao BR, Geldof AA, van der Wilt CL, de Voogt HJ | title = Efficacy and advantages in the use of low doses of Anandron and estrogen combination in the treatment of prostate cancer | journal = The Prostate | volume = 13 | issue = 1 | pages = 69–78 | date = 1988 | pmid = 3420036 | doi = 10.1002/pros.2990130108 | s2cid = 23553575 }}

Nilutamide has been studied in the treatment of advanced breast cancer.{{cite journal | vauthors = Chia K, O'Brien M, Brown M, Lim E | title = Targeting the androgen receptor in breast cancer | journal = Current Oncology Reports | volume = 17 | issue = 2 | pages = 4 | date = February 2015 | pmid = 25665553 | doi = 10.1007/s11912-014-0427-8 | s2cid = 5174768 | url = http://handle.unsw.edu.au/1959.4/61991 }}{{cite journal | vauthors = Millward MJ, Cantwell BM, Dowsett M, Carmichael J, Harris AL | title = Phase II clinical and endocrine study of Anandron (RU-23908) in advanced post-menopausal breast cancer | journal = British Journal of Cancer | volume = 63 | issue = 5 | pages = 763–764 | date = May 1991 | pmid = 1903951 | pmc = 1972372 | doi = 10.1038/bjc.1991.170 }}

{{Reflist}}

{{refbegin|30em}}

• {{cite journal | vauthors = Raynaud JP, Bonne C, Moguilewsky M, Lefebvre FA, Bélanger A, Labrie F | title = The pure antiandrogen RU 23908 (Anandron), a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review | journal = The Prostate | volume = 5 | issue = 3 | pages = 299–311 | year = 1984 | pmid = 6374639 | doi = 10.1002/pros.2990050307 | s2cid = 85417869 }}
• {{cite journal | vauthors = Moguilewsky M, Bertagna C, Hucher M | title = Pharmacological and clinical studies of the antiandrogen Anandron | journal = Journal of Steroid Biochemistry | volume = 27 | issue = 4–6 | pages = 871–875 | year = 1987 | pmid = 3320565 | doi = 10.1016/0022-4731(87)90162-2 }}
• {{cite journal | vauthors = Du Plessis DJ | title = Castration plus nilutamide vs castration plus placebo in advanced prostate cancer. A review | journal = Urology | volume = 37 | issue = 2 Suppl | pages = 20–24 | year = 1991 | pmid = 1992599 | doi = 10.1016/0090-4295(91)80097-q }}
• {{cite journal | vauthors = Creaven PJ, Pendyala L, Tremblay D | title = Pharmacokinetics and metabolism of nilutamide | journal = Urology | volume = 37 | issue = 2 Suppl | pages = 13–19 | year = 1991 | pmid = 1992598 | doi = 10.1016/0090-4295(91)80096-p }}
• {{cite journal | vauthors = Harris MG, Coleman SG, Faulds D, Chrisp P | title = Nilutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer | journal = Drugs & Aging | volume = 3 | issue = 1 | pages = 9–25 | year = 1993 | pmid = 8453188 | doi = 10.2165/00002512-199303010-00002 | s2cid = 262029302 }}
• {{cite journal | vauthors = Dole EJ, Holdsworth MT | title = Nilutamide: an antiandrogen for the treatment of prostate cancer | journal = The Annals of Pharmacotherapy | volume = 31 | issue = 1 | pages = 65–75 | date = January 1997 | pmid = 8997470 | doi = 10.1177/106002809703100112 | s2cid = 20347526 }}
• {{cite journal | vauthors = Iversen P, Melezinek I, Schmidt A | title = Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function | journal = BJU International | volume = 87 | issue = 1 | pages = 47–56 | date = January 2001 | pmid = 11121992 | doi = 10.1046/j.1464-410x.2001.00988.x | s2cid = 28215804 | doi-access = free }}

{{refend}}

{{Androgens and antiandrogens}}

{{Androgen receptor modulators}}

Category:CYP17A1 inhibitors

Category:Disulfiram-like drugs

Category:Hepatotoxins

Category:Hormonal antineoplastic drugs

Category:Hydantoins

Category:Nitrobenzene derivatives

Category:Nonsteroidal antiandrogens

Category:Progonadotropins

Category:Prostate cancer

Category:Trifluoromethyl compounds