Nilutamide

Nilutamide

Clinical data
Pronunciation	nye-LOO-tah-mide [1]
Trade names	Nilandron, Anandron
Other names	RU-23908
AHFS/Drugs.com	Monograph
MedlinePlus	a697044
Routes of administration	By mouth [2]
Drug class	Nonsteroidal antiandrogen
ATC code	L02BB02 ( WHO )
Legal status
Legal status	US: WARNING [3] In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	Good [2]
Protein binding	80–84% [4]
Metabolism	Liver (CYP2C19, FMO Tooltip flavin-containing monooxygenase) [2] [4]
Metabolites	At least 5, some active [4] [5]
Elimination half-life	Mean: 56 hours (~2 days) [6] Range: 23–87 hours [6]
Excretion	Urine: 62% [2] [4] Feces: <10% [2] [4]
Identifiers
IUPAC name 5,5-Dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione
CAS Number	63612-50-0  Y
PubChem CID	4493
IUPHAR/BPS	2864
DrugBank	DB00665  Y
ChemSpider	4337  Y
UNII	51G6I8B902
KEGG	D00965  Y
ChEBI	CHEBI:7573  Y
ChEMBL	ChEMBL1274  Y
CompTox Dashboard (EPA)	DTXSID3034165
ECHA InfoCard	100.153.268
Chemical and physical data
Formula	C12H10F3N3O4
Molar mass	317.224 g·mol−1
3D model (JSmol)	Interactive image
Melting point	149 °C (300 °F)
SMILES CC1(C(=O)N(C(=O)N1)C2=CC(=C(C=C2)[N+](=O)[O-])C(F)(F)F)C
InChI InChI=1S/C12H10F3N3O4/c1-11(2)9(19)17(10(20)16-11)6-3-4-8(18(21)22)7(5-6)12(13,14)15/h3-5H,1-2H3,(H,16,20) Y Key:XWXYUMMDTVBTOU-UHFFFAOYSA-N Y
(verify)

Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer. ^{[7] [8] [9] [10] [11] [12]} It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women. ^{[13] [14] [15] [16]} It is taken by mouth. ^[4]

Side effects in men include breast tenderness and enlargement, feminization, sexual dysfunction, and hot flashes. ^{[17] [18] [19] [20]} Nausea, vomiting, visual disturbances, alcohol intolerance, elevated liver enzymes, and lung disease can occur in both sexes. ^{[20] [21] [18] [22] [23] [24]} Rarely, nilutamide can cause respiratory failure and liver damage. ^{[17] [20]} These unfavorable side effects, along with a number of associated cases of death, have limited the use of nilutamide. ^{[12] [25] [26]}

Nilutamide acts as a selective antagonist of the androgen receptor (AR), preventing the effects of androgens like testosterone and dihydrotestosterone (DHT) in the body. ^{[27] [13]} Because most prostate cancer cells rely on these hormones for growth and survival, nilutamide can slow the progression of prostate cancer and extend life in men with the disease. ^[13]

Nilutamide was discovered in 1977 and was first introduced for medical use in 1987. ^{[8] [28] [29] [6]} It became available in the United States in 1996. ^{[30] [31] [32]} The drug has largely been replaced by newer and improved NSAAs, namely bicalutamide and enzalutamide, due to their better efficacy, tolerability, and safety, and is now rarely used. ^[33]

It is on the World Health Organization's List of Essential Medicines. ^[34]

Medical uses

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. ^{[26] [35]} It is not indicated as a monotherapy in prostate cancer. ^[26] Only one small non-comparative study has assessed nilutamide as a monotherapy in prostate cancer. ^[36]

Nilutamide has been used to prevent the effects of the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer. ^{[37] [38] [39]}

Transgender hormone therapy

Nilutamide has been studied for use as a component of feminizing hormone therapy for transgender women. ^{[13] [14]} It has been assessed in at least five small clinical studies for this purpose in treatment-naive subjects. ^{[14] [40] [41] [42] [43] [44]} 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, ^[41] including breast development, decreased body hair (though not facial hair), ^[40] decreased morning erections and sex drive, ^[42] and positive psychological and emotional changes. ^{[42] [45]} Signs of breast development occurred in all subjects within 6 weeks and were associated with increased nipple sensitivity, ^{[44] [41] [42]} and along with decreased hair growth, were the earliest sign of feminization. ^[41]

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. ^{[43] [44] [46]} In addition, readily apparent histological changes were observed in the testes, including a reduction in tubular and interstitial cells. ^[43]

Nilutamide was found to more than double luteinizing hormone (LH) and testosterone levels and to triple estradiol levels. ^{[40] [41] [43]} In contrast, follicle-stimulating hormone levels remained unchanged. ^{[41] [43]} A slight but significant increase in prolactin levels was observed, and levels of sex hormone-binding globulin increased as well. ^{[41] [43]} 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. ^{[40] [41]} 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. ^{[40] [41]}

Skin conditions

Nilutamide has been assessed in the treatment of acne and seborrhea in women in at least one small clinical study. ^{[15] [16]} 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." ^{[15] [16]}

Available forms

Nilutamide is available in the form of 50 and 150 mg oral tablets. ^[47]

Side effects

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. ^{[18] [19] [20]} Also, nausea (24–27%), vomiting, constipation (20%), and insomnia (16%) may occur with nilutamide. ^[20] 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. ^{[48] [49] [50] [51]}

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, ^[21] a disulfiram-like ^[18] alcohol intolerance (19%), interstitial pneumonitis (0.77–2.4%) ^{[33] [52] [53]} (which can result in dyspnea (1%) as a secondary effect and can progress to pulmonary fibrosis), ^[22] and hepatitis (1%), and has a higher incidence of nausea and vomiting compared to other NSAAs. ^{[12] [26] [20] [54]} 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. ^{[55] [56]} There is a case report of simultaneous liver and lung toxicity in a nilutamide-treated patient. ^[57]

There is also a risk of hepatotoxicity with nilutamide, though occurrence is very rare and the risk is significantly less than with flutamide. ^{[6] [58]} The incidence of abnormal liver function tests (e.g., elevated liver enzymes) has been variously reported as 2 to 33% with nilutamide. ^{[59] [1]} For comparison, the risk of elevated liver enzymes has been reported as 4 to 62% in the case of flutamide. ^{[59] [23] [6]} The risk of hepatotoxicity with nilutamide has been described as far less than with flutamide. ^[1] Fulminant hepatic failure has been reported for nilutamide, with fatal outcome. ^{[6] [60] [61] [62]} 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. ^[63] 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. ^{[62] [64] [65]} The nitro group of nilutamide has been theorized to be involved in both its hepatotoxicity and its pulmonary toxicity. ^{[65] [66]}

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Side effects of combined androgen blockade with nilutamide and surgical castration

Class	Side effect	Nilutamide 150 mg/day + orchiectomy (n = 225) (%)a,b	Placebo + orchi- ectomy (n = 232) (%)a,b
Cardiovascular system	Hypertension	5.3	2.6
Digestive system	Nausea	9.8	6.0
	Constipation	7.1	3.9
Endocrine system	Hot flashes	28.4	22.4
Metabolic and nutritional system	Increased aspartate transaminase	8.0	3.9
	Increased alanine transaminase	7.6	4.3
Nervous system	Dizziness	7.1	3.4
Respiratory system	Dyspnea	6.2	7.3
Special senses	Impaired adaptation to darkness	12.9	1.3
	Abnormal vision	6.7	1.7
Urogenital system	Urinary tract infection	8.0	9.1
Overall		86	81
Footnotes:a = Phase III studies of combined androgen blockade (nilutamide + orchiectomy) in men with advanced prostate cancer. b = Incidence ≥5% regardless of causality. Sources: See template.

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

Class	Side effect	Nilutamide 150 mg/day + leuprorelin (n = 209) (%)a,b	Placebo + leupro- relin (n = 202) (%)a,b
Body as a whole	Pain	26.8	27.7
	Headache	13.9	10.4
	Asthenia	19.1	20.8
	Back pain	11.5	16.8
	Abdominal pain	10.0	5.4
	Chest pain	7.2	4.5
	Flu syndrome	7.2	3.0
	Fever	5.3	6.4
Cardiovascular system	Hypertension	9.1	9.9
Digestive system	Nausea	23.9	8.4
	Constipation	19.6	16.8
	Anorexia	11.0	6.4
	Dyspepsia	6.7	4.5
	Vomiting	5.7	4.0
Endocrine system	Hot flashes	66.5	59.4
	Erectile dysfunction	11.0	12.9
	Decreased libido	11.0	4.5
Hemic and lymphatic system	Anemia	7.2	6.4
Metabolic and nutritional system	Increased aspartate transaminase	12.9	13.9
	Peripheral edema	12.4	17.3
	Increased alanine transaminase	9.1	8.9
Musculoskeletal system	Bone pain	6.2	5.0
Nervous system	Insomnia	16.3	15.8
	Dizziness	10.0	11.4
	Depression	8.6	7.4
	Hypesthesia	5.3	2.0
Respiratory system	Dyspnea	10.5	7.4
	Upper respiratory infection	8.1	10.9
	Pneumonia	5.3	3.5
Skin and appendages	Sweating	6.2	3.0
	Decreased body hair	5.7	0.5
	Dry skin	5.3	2.5
	Rash	5.3	4.0
Special senses	Impaired adaptation to darkness	56.9	5.4
	Chromatopsia	8.6	0.0
	Impaired adaptation to light	7.7	1.0
	Abnormal vision	6.2	4.5
Urogenital system	Testicular atrophy	16.3	12.4
	Gynecomastia	10.5	11.9
	Urinary tract infection	8.6	21.3
	Hematuria	8.1	7.9
	Urinary tract disorder	7.2	10.4
	Nocturia	6.7	6.4
Overall		99.5	98.5
Footnotes:a = Phase III studies of combined androgen blockade (nilutamide + GnRH agonist) in men with advanced prostate cancer. b = Incidence ≥5% regardless of causality. Sources: See template.

Pharmacology

Pharmacodynamics

Antiandrogenic activity

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Affinities ^{[a] [67]}

Compound	RBA Tooltip Relative binding affinity [b]
Metribolone	100
Dihydrotestosterone	85
Cyproterone acetate	7.8
Bicalutamide	1.4
Nilutamide	0.9
Hydroxyflutamide	0.57
Flutamide	<0.0057
Notes: At androgen receptors; measured in human prostate tissue. Relative to Metribolone, which is by definition 100%

Nilutamide acts as a selective competitive silent antagonist of the AR (IC₅₀ = 412 nM), ^[27] which prevents androgens like testosterone and DHT from activating the receptor. ^[13] 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. ^{[68] [69] [70]} Similarly to 2-hydroxyflutamide, but unlike bicalutamide, nilutamide is able to weakly activate the AR at high concentrations. ^[69] It does not inhibit 5α-reductase. ^[71]

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. ^[29]

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

Species	IC50 Tooltip Half maximal inhibitory concentration (nM)			RBA Tooltip Relative binding affinity (ratio)
	Bicalutamide	2-Hydroxyflutamide	Nilutamide	Bica / 2-OH-flu	Bica / nilu	Ref
Rat	190	700	ND	4.0	ND	[72]
Rat	~400	~900	~900	2.3	2.3	[73]
Rat	ND	ND	ND	3.3	ND	[74]
Rata	3595	4565	18620	1.3	5.2	[75]
Human	~300	~700	~500	2.5	1.6	[76]
Human	~100	~300	ND	~3.0	ND	[77]
Humana	2490	2345	5300	1.0	2.1	[75]
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. ^[78] It has also been found to inhibit the enzyme CYP17A1 (17α-hydroxylase/17,20-lyase) in vitro and thus the biosynthesis of androgens. ^{[79] [80]} However, nilutamide monotherapy significantly increases testosterone levels in vivo, so the clinical significance of this finding is uncertain. ^{[79] [80]}

Pharmacokinetics

Nilutamide has an elimination half-life of 23 to 87 hours, with a mean of 56 hours, ^[6] or about two days; this allows for once-daily administration. ^[12] 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). ^[81] 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). ^[82]

Chemistry

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

History

Nilutamide was developed by Roussel and was first described in 1977. ^{[8] [28] [29]} It was first introduced for medical use in 1987 in France ^{[6] [83]} and was the second NSAA to be marketed, with flutamide preceding it and bicalutamide following it in 1995. ^{[12] [84]} It was not introduced until 1996 in the United States. ^{[30] [31] [32]}

Society and culture

Generic names

Nilutamide is the generic name of the drug and its INN Tooltip International Nonproprietary Name, USAN Tooltip United States Adopted Name, BAN Tooltip British Approved Name, and DCF Tooltip Dénomination Commune Française. ^{[8] [9] [10] [11]}

Brand names

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. ^{[9] [11]}

Availability

Nilutamide is or has been available in the United States, Canada, Australia, Europe, Latin America, Egypt, and Lebanon. ^{[9] [11]} 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. ^{[9] [11]} in Latin America, it is or has been available in Argentina, Brazil, and Mexico. ^{[9] [11]}

Research

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. ^[85]

Nilutamide has been studied in the treatment of advanced breast cancer. ^{[86] [87]}

References

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36. Anderson J (March 2003). "The role of antiandrogen monotherapy in the treatment of prostate cancer". BJU International. 91 (5): 455–461. doi:10.1046/j.1464-410X.2003.04026.x. PMID   12603397. S2CID   8639102. 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.
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46. Drugs & Aging. Adis International. 1993. Archived from the original on 10 January 2023. Retrieved 2 April 2018. 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).
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63. Chitturi S, Farrell GC (2013). "Adverse Effects of Hormones and Hormone Antagonists on the Liver". Drug-Induced Liver Disease. Vol. 3. Academic Press. pp. 605–619. doi:10.1016/B978-0-12-387817-5.00033-9. ISBN   9780123878175. PMID   11096606. 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].{{cite book}}: |journal= ignored (help)
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Further reading

• Raynaud JP, Bonne C, Moguilewsky M, Lefebvre FA, Bélanger A, Labrie F (1984). "The pure antiandrogen RU 23908 (Anandron), a candidate of choice for the combined antihormonal treatment of prostatic cancer: a review". The Prostate. 5 (3): 299–311. doi:10.1002/pros.2990050307. PMID   6374639. S2CID   85417869.
• Moguilewsky M, Bertagna C, Hucher M (1987). "Pharmacological and clinical studies of the antiandrogen Anandron". Journal of Steroid Biochemistry. 27 (4–6): 871–875. doi:10.1016/0022-4731(87)90162-2. PMID   3320565.
• Du Plessis DJ (1991). "Castration plus nilutamide vs castration plus placebo in advanced prostate cancer. A review". Urology. 37 (2 Suppl): 20–24. doi:10.1016/0090-4295(91)80097-q. PMID   1992599.
• Creaven PJ, Pendyala L, Tremblay D (1991). "Pharmacokinetics and metabolism of nilutamide". Urology. 37 (2 Suppl): 13–19. doi:10.1016/0090-4295(91)80096-p. PMID   1992598.
• Harris MG, Coleman SG, Faulds D, Chrisp P (1993). "Nilutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in prostate cancer". Drugs & Aging. 3 (1): 9–25. doi:10.2165/00002512-199303010-00002. PMID   8453188. S2CID   262029302.
• Dole EJ, Holdsworth MT (January 1997). "Nilutamide: an antiandrogen for the treatment of prostate cancer". The Annals of Pharmacotherapy. 31 (1): 65–75. doi:10.1177/106002809703100112. PMID   8997470. S2CID   20347526.
• Iversen P, Melezinek I, Schmidt A (January 2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU International. 87 (1): 47–56. doi: 10.1046/j.1464-410x.2001.00988.x . PMID   11121992. S2CID   28215804.