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. 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.
Nilutamide has been used to prevent the effects of the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer.
Nilutamide has been assessed in the treatment of acne and seborrhea in women in at least one small clinical study. 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."
Notes: Human prostate tissue used for the assays. Sources: See template.
Nilutamide acts as a selectivecompetitivesilent antagonist of the AR (IC50 = 412 nM), which prevents androgens like testosterone and DHT from activating the receptor. 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. Nilutamide has approximately the same affinity for the AR as 2-hydroxyflutamide. Similarly to 2-hydroxyflutamide, but unlike bicalutamide, nilutamide is able to weakly activate the AR at high concentrations. It does not inhibit 5α-reductase.
Notes: (1): Reference ligands (100%) were testosterone for the AR, progesterone for the PR, estradiol for the ER, dexamethasone for the GR, and aldosterone for the MR. (2): Tissues were rat prostate (AR), rabbit uterus (PR), mouse uterus (ER), rat thymus (GR), and rat kidney (MR). (3): Incubation times (0°C) were 24 hours (AR, a), 2 hours (PR, ER), 4 hours (GR), and 1 hour (MR). (4): Assay methods were different for bicalutamide for receptors besides the AR. Sources: See template.
Relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor
Footnotes:a = Controversial data. Sources: See template.
Cytochrome P450 inhibition
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. It has also been found to inhibit the enzyme CYP17A1 (17α-hydroxylase/17,20-lyase) in vitro and thus the biosynthesis of androgens. 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). It is metabolized by CYP2C19, with at least five metabolites. Virtually all of the antiandrogenic activity of nilutamide comes from the parent drug (as opposed to metabolites).
Nilutamide was developed by Roussel and was first described in 1977. It was first introduced for medical use in 1987 in France and was the second NSAA to be marketed, with flutamide preceding it and bicalutamide following it in 1995. It was not introduced until 1996 in the United States.
^ abc"Nilutamide - LiverTox". National Institutes of Health. Retrieved 24 September 2018. 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.
^ abcdefghKolvenbag, Geert J. C. M.; Furr, Barrington J. A. (2009). "Nonsteroidal Antiandrogens". In V. Craig Jordan; Barrington J. A. Furr (eds.). Hormone Therapy in Breast and Prostate Cancer. Humana Press. pp. 347–368. doi:10.1007/978-1-59259-152-7_16. ISBN978-1-60761-471-5. 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.
^ abcCouzinet B, Thomas G, Thalabard JC, Brailly S, Schaison G (1989). "Effects of a pure antiandrogen on gonadotropin secretion in normal women and in polycystic ovarian disease". Fertil. Steril. 52 (1): 42–50. doi:10.1016/s0015-0282(16)60786-0. PMID2744186.
^ abLabrie, Fernand; Lagacé, Lisette; Ferland, Louise; Kelly, Paul A.; Drouin, Jacques; Massicotte, Jocelyne; Bonne, Claude; Raynaud, Jean-Pierre; Dorrington, Jennifer H. (1978). "Interactions Between LHRH, Sex Steroids and "Inhibin" in the Control of LH and FSH Secretion". International Journal of Andrology. 1 (s2a): 81–101. doi:10.1111/j.1365-2605.1978.tb00008.x. ISSN0105-6263.
^ abRaynaud JP, Bonne C, Bouton MM, Lagace L, Labrie F (1979). "Action of a non-steroid anti-androgen, RU 23908, in peripheral and central tissues". J. Steroid Biochem. 11 (1A): 93–9. doi:10.1016/0022-4731(79)90281-4. PMID385986.
^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. PMID12603397. 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) . 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 . 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.
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^ abcdeAsscheman, 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. ISSN0307-6938. PMID2612040.
^ abcdvan 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. ISSN0004-0002. PMID2751416.
^ abcdefGooren, 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. ISSN0021-972X. PMID3102546.
^ abcDe 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. ISSN0270-4137. PMID2960959.
^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. ISSN0890-7064.
^Drugs & Aging. Adis International. 1993. 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).
^Bautista-Vidal, C.; Barnoiu, O.; García-Galisteo, E.; Gómez-Lechuga, P.; Baena-González, V. (2014). "Treatment of gynecomastia in patients with prostate cancer and androgen deprivation". Actas Urológicas Españolas (English Edition). 38 (1): 34–40. doi:10.1016/j.acuroe.2013.10.002. ISSN2173-5786. [...] the frequency of gynecomastia with antiandrogens in monotherapy is [...] around [...] 79% with nilutamide [...]
^Deepinder, Fnu; Braunstein, Glenn D (2012). "Drug-induced gynecomastia: an evidence-based review". Expert Opinion on Drug Safety. 11 (5): 779–795. doi:10.1517/14740338.2012.712109. ISSN1474-0338. 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 [...]
^Michalopoulos, Nikolaos V.; Keshtgar, Mohammed R. (2012). "Gynecomastia Induced by Prostate-Cancer Treatment". New England Journal of Medicine. 367 (15): 1449. doi:10.1056/NEJMicm1209166. ISSN0028-4793. 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.
^Di Lorenzo G, Autorino R, Perdonà S, De Placido S (December 2005). "Management of gynaecomastia in patients with prostate cancer: a systematic review". Lancet Oncol. 6 (12): 972–9. doi:10.1016/S1470-2045(05)70464-2. PMID16321765.
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^ abMerwat, 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. ISSN0163-2116. PMID18688719. 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 .
^Chitturi, Shivakumar; Farrell, Geoffrey C (2013). "Adverse Effects of Hormones and Hormone Antagonists on the Liver". Drug-Induced Liver Disease. pp. 605–619. doi:10.1016/B978-0-12-387817-5.00033-9. ISBN9780123878175. 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].
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