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,FMOTooltip flavin-containing monooxygenase)[2][4]
Metabolites	At least 5, some active[4][5]
Eliminationhalf-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
PubChemCID	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
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Nilutamide, sold under the brand namesNilandron andAnandron, is anonsteroidal antiandrogen (NSAA) which is used in the treatment ofprostate cancer.^{[8][9][10][11][12][13]} It has also been studied as a component offeminizing hormone therapy fortransgender women and to treatacne andseborrhea in women.^{[14][15][16][17]} It is takenby mouth.^[4]

Side effects in men includebreast tenderness andenlargement,feminization,sexual dysfunction, andhot flashes.^{[18][19][20][21]}Nausea,vomiting,visual disturbances,alcohol intolerance,elevated liver enzymes, andlung disease can occur in both sexes.^{[21][22][19][23][24][25]} Rarely, nilutamide can causerespiratory failure andliver damage.^[18][21] These unfavorable side effects, along with a number of associated cases of death, have limited the use of nilutamide.^[13][26][27]

Nilutamide acts as aselectiveantagonist of theandrogen receptor (AR), preventing the effects ofandrogens liketestosterone anddihydrotestosterone (DHT) in the body.^[28][14] Because most prostate cancercells rely on thesehormones forgrowth andsurvival, nilutamide can slow the progression of prostate cancer and extend life in men with the disease.^[14]

Nilutamide was discovered in 1977 and was first introduced for medical use in 1987.^{[9][29][30][6]} It became available in the United States in 1996.^[31][32][33] The drug has largely been replaced by newer and improved NSAAs, namelybicalutamide andenzalutamide, due to their betterefficacy,tolerability, andsafety, and is now rarely used.^[34]

It is on theWorld Health Organization's List of Essential Medicines.^[35]

Nilutamide is used in prostate cancer in combination with agonadotropin-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.^[27][36] It is not indicated as amonotherapy in prostate cancer.^[27] Only one small non-comparative study has assessed nilutamide as a monotherapy in prostate cancer.^[37]

Nilutamide has been used to prevent the effects of thetestosterone flare at the start of GnRH agonist therapy in men with prostate cancer.^[38][39][40]

Nilutamide has been studied for use as a component offeminizing hormone therapy fortransgender women.^[14][15] It has been assessed in at least five smallclinical studies for this purpose in treatment-naive subjects.^{[15][41][42][43][44][45]} In these studies, nilutamide monotherapy at a dosage of 300 mg/day, induced observable signs of clinicalfeminization in young transgender women (age range 19–33 years) within 8 weeks,^[42] includingbreast development, decreasedbody hair (though notfacial hair),^[41] decreasedmorning erections andsex drive,^[43] and positive psychological and emotional changes.^[43][46] Signs of breast development occurred in all subjects within 6 weeks and were associated with increasednipple sensitivity,^[45][42][43] and along with decreased hair growth, were the earliest sign of feminization.^[42]

Nilutamide did not change the size of theprostate gland (which is the same as with high-dosagecyproterone acetate andethinylestradiol treatment for as long as 18 months), but was found to alter itshistology, including increasedstromal tissue with a significant reduction inacini and atrophicepithelial cells, indicating glandularatrophy.^[44][45][47] In addition, readily apparent histological changes were observed in thetestes, including a reduction intubular andinterstitial cells.^[44]

Nilutamide was found to more than doubleluteinizing hormone (LH) andtestosterone levels and to tripleestradiol levels.^[41][42][44] In contrast,follicle-stimulating hormone levels remained unchanged.^[42][44] A slight but significant increase inprolactin levels was observed, and levels ofsex hormone-binding globulin increased as well.^[42][44] 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 thecastrate range.^[41][42] Both nilutamide alone and the combination of nilutamide andestrogen were regarded as resulting in effective and favorable antiandrogen action and feminization in transgender women.^[41][42]

Nilutamide has been assessed in the treatment ofacne andseborrhea in women in at least one small clinical study.^[16][17] 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."^[16][17]

Nilutamide is available in the form of 50 and 150 mgoraltablets.^[48]

Generalside effects of NSAAs, including nilutamide, includegynecomastia,breast pain/tenderness,hot flashes (67%),depression,fatigue,sexual dysfunction (including loss oflibido anderectile dysfunction), decreasedmuscle mass, and decreasedbone mass with an associated increase infractures.^[19][20][21] Also,nausea (24–27%),vomiting,constipation (20%), andinsomnia (16%) may occur with nilutamide.^[21] 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.^{[49][50][51][52]}

Relative to other NSAAs, nilutamide has been uniquely associated with mild and reversiblevisual disturbances (31–58%) includingdelayed ocular adaptation to darkness and impairedcolor vision,^[22] adisulfiram-like^[19]alcoholintolerance (19%),interstitial pneumonitis (0.77–2.4%)^[34][53][54] (which can result indyspnea (1%) as a secondary effect and can progress topulmonary fibrosis),^[23] andhepatitis (1%), and has a higher incidence of nausea and vomiting compared to other NSAAs.^{[13][27][21][55]} The incidence of interstitial pneumonitis with nilutamide has been found to be much higher inJapanese patients (12.6%), warranting particular caution inAsian individuals.^[56][57] There is a case report of simultaneous liver and lung toxicity in a nilutamide-treated patient.^[58]

There is also a risk ofhepatotoxicity with nilutamide, though occurrence is very rare and the risk is significantly less than with flutamide.^[6][59] The incidence of abnormalliver function tests (e.g.,elevated liver enzymes) has been variously reported as 2 to 33% with nilutamide.^[60][1] For comparison, the risk of elevated liver enzymes has been reported as 4 to 62% in the case offlutamide.^[60][24][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][61][62][63]} Between 1986 and 2003, the numbers of published cases of hepatotoxicity for antiandrogens totaled 46 for flutamide, 21 forcyproterone acetate, 4 for nilutamide, and 1 forbicalutamide.^[64] Similarly to flutamide, nilutamide exhibitsmitochondrialtoxicity inhepatocytes by inhibitingrespiratory complex I (NADH ubiquinone oxidoreductase) (though notrespiratory complexes II, III, or IV) in theelectron transport chain, resulting in reducedATP andglutathione production and thus decreased hepatocyte survival.^[63][65][66] Thenitrogroup of nilutamide has been theorized to be involved in both its hepatotoxicity and itspulmonary toxicity.^[66][67]

Nilutamide acts as aselectivecompetitivesilent antagonist of the AR (IC₅₀ = 412 nM),^[28] which prevents androgens like testosterone and DHT from activating the receptor.^[14] The affinity of nilutamide for the AR is about 1 to 4% of that of testosterone and is similar to that ofbicalutamide and2-hydroxyflutamide.^[69][70][71] Similarly to 2-hydroxyflutamide, but unlike bicalutamide, nilutamide is able to weakly activate the AR at high concentrations.^[70] It does not inhibit5α-reductase.^[72]

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, andprolactin levels due to inhibition of AR-mediated suppression ofsteroidogenesis vianegative feedback on thehypothalamic–pituitary–gonadal axis.^[14] As such, though nilutamide is still effective as an antiandrogen as a monotherapy, it is given in combination with a GnRH analogue such asleuprorelin in prostate cancer to suppress androgen concentrations to castrate levels in order to attainmaximal androgen blockade (MAB).^[14]

Like flutamide and bicalutamide, nilutamide is able to cross theblood–brain barrier and hascentral antiandrogen actions.^[30]

Nilutamide is known to inhibit severalcytochrome P450 enzymes, includingCYP1A2,CYP2C9, andCYP3A4, and can result in increased levels of medications that aremetabolized by theseenzymes.^[79] It has also been found to inhibit the enzymeCYP17A1 (17α-hydroxylase/17,20-lyase)in vitro and thus thebiosynthesis of androgens.^[80][81] However, nilutamide monotherapy significantly increases testosterone levelsin vivo, so the clinical significance of this finding is uncertain.^[80][81]

Nilutamide has anelimination half-life of 23 to 87 hours, with a mean of 56 hours,^[6] or about two days; this allows for once-daily administration.^[13]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).^[82] It ismetabolized byCYP2C19, with at least fivemetabolites.^[5] Virtually all of the antiandrogenic activity of nilutamide comes from the parent drug (as opposed to metabolites).^[83]

Nilutamide is structurally related to thefirst-generation NSAAsflutamide andbicalutamide as well as to thesecond-generation NSAAsenzalutamide andapalutamide.

Nilutamide was developed byRoussel and was first described in 1977.^[9][29][30] It was first introduced for medical use in 1987 inFrance^[6][84] and was the second NSAA to be marketed, with flutamide preceding it and bicalutamide following it in 1995.^[13][85] It was not introduced until 1996 in theUnited States.^[31][32][33]

Nilutamide is thegeneric name of the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name, andDCFTooltip Dénomination Commune Française.^{[9][10][11][12]}

Nilutamide is marketed under the brand name Nilandron in theUnited States and under the brand name Anandron elsewhere in the world such as inAustralia,Canada,Europe, andLatin America.^[10][12]

Nilutamide is or has been available in the United States, Canada, Australia, Europe, Latin America,Egypt, andLebanon.^[10][12] In Europe, it is or has been available inBelgium,Croatia, theCzech Republic,Finland,France, theNetherlands,Norway,Poland,Portugal,Serbia,Sweden,Switzerland, andYugoslavia.^[10][12] in Latin America, it is or has been available inArgentina,Brazil, andMexico.^[10][12]

The combination of anestrogen and nilutamide as a form ofcombined androgen blockade for the treatment of prostate cancer has been studied in animals.^[86]

Nilutamide has been studied in the treatment of advanced breast cancer.^[87][88]

• CYP17A1 inhibitors
• Disulfiram-like drugs
• Hepatotoxins
• Hormonal antineoplastic drugs
• Hydantoins
• Nitrobenzene derivatives
• Nonsteroidal antiandrogens
• Progonadotropins
• Prostate cancer
• Trifluoromethyl compounds

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