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Nilutamide

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Nilutamide
Clinical data
Pronunciationnye-LOO-tah-mide[1]
Trade namesNilandron, Anandron
Other namesRU-23908
AHFS/Drugs.comMonograph
MedlinePlusa697044
Routes of
administration		By mouth[2]
Drug classNonsteroidal antiandrogen
ATC code
Legal status
Legal status
Pharmacokineticdata
BioavailabilityGood[2]
Protein binding80–84%[4]
MetabolismLiver(CYP2C19,FMOTooltip flavin-containing monooxygenase)[2][4]
MetabolitesAt least 5, some active[4][5]
Eliminationhalf-lifeMean: 56 hours (~2 days)[6]
Range: 23–87 hours[6]
ExcretionUrine:62%[2][4]
Feces:<10%[2][4]
Identifiers
  • 5,5-Dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione
CAS Number
PubChemCID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard(EPA)
ECHA InfoCard100.153.268Edit this at Wikidata
Chemical and physical data
FormulaC12H10F3N3O4
Molar mass317.224g·mol−1
3D model (JSmol)
Melting point149 °C (300 °F)
  • CC1(C(=O)N(C(=O)N1)C2=CC(=C(C=C2)[N+](=O)[O-])C(F)(F)F)C
  • 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)checkY
  • Key:XWXYUMMDTVBTOU-UHFFFAOYSA-NcheckY
(verify)

Nilutamide,sold under the brand namesNilandronandAnandron,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 therapyfortransgender womenand to treatacneandseborrheain women.[14][15][16][17]It is takenby mouth.[4]

Side effectsin men includebreast tendernessandenlargement,feminization,sexual dysfunction,andhot flashes.[18][19][20][21]Nausea,vomiting,visual disturbances,alcohol intolerance,elevated liver enzymes,andlung diseasecan occur in both sexes.[21][22][19][23][24][25]Rarely, nilutamide can causerespiratory failureandliver 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 aselectiveantagonistof theandrogen receptor(AR), preventing the effects ofandrogensliketestosteroneanddihydrotestosterone(DHT) in the body.[28][14]Because most prostate cancercellsrely on thesehormonesforgrowthandsurvival,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, namelybicalutamideandenzalutamide,due to their betterefficacy,tolerability,andsafety,and is now rarely used.[34]

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

Medical uses

[edit]

Prostate cancer

[edit]

Nilutamide is used in prostate cancer in combination with agonadotropin-releasing hormone(GnRH)analogueat 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 amonotherapyin 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 thetestosteroneflare at the start of GnRH agonist therapy in men with prostate cancer.[38][39][40]

Transgender hormone therapy

[edit]

Nilutamide has been studied for use as a component offeminizing hormone therapyfortransgender women.[14][15]It has been assessed in at least five smallclinical studiesfor 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 clinicalfeminizationin young transgender women (age range 19–33 years) within 8 weeks,[42]includingbreast development,decreasedbody hair(though notfacial hair),[41]decreasedmorning erectionsandsex 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 acetateandethinylestradioltreatment for as long as 18 months), but was found to alter itshistology,including increasedstromal tissuewith a significant reduction inaciniand atrophicepithelial cells,indicating glandularatrophy.[44][45][47]In addition, readily apparent histological changes were observed in thetestes,including a reduction intubularandinterstitial cells.[44]

Nilutamide was found to more than doubleluteinizing hormone(LH) andtestosteronelevels and to tripleestradiollevels.[41][42][44]In contrast,follicle-stimulating hormonelevels remained unchanged.[42][44]A slight but significant increase inprolactinlevels was observed, and levels ofsex hormone-binding globulinincreased 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 thecastraterange.[41][42]Both nilutamide alone and the combination of nilutamide andestrogenwere regarded as resulting in effective and favorable antiandrogen action and feminization in transgender women.[41][42]

Skin conditions

[edit]

Nilutamide has been assessed in the treatment ofacneandseborrheain 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]

Available forms

[edit]

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

Side effects

[edit]

Generalside effectsof NSAAs, including nilutamide, includegynecomastia,breast pain/tenderness,hot flashes(67%),depression,fatigue,sexual dysfunction(including loss oflibidoanderectile dysfunction), decreasedmusclemass, and decreasedbonemass 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 darknessand 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 inJapanesepatients (12.6%), warranting particular caution inAsianindividuals.[56][57]There is a case report of simultaneous liver and lung toxicity in a nilutamide-treated patient.[58]

There is also a risk ofhepatotoxicitywith 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 failurehas 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 exhibitsmitochondrialtoxicityinhepatocytesby inhibitingrespiratory complex I(NADH ubiquinone oxidoreductase) (though notrespiratory complexes II, III, or IV) in theelectron transport chain,resulting in reducedATPandglutathioneproduction and thus decreased hepatocyte survival.[63][65][66]Thenitrogroupof nilutamide has been theorized to be involved in both its hepatotoxicity and itspulmonary toxicity.[66][67]

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
Metabolicandnutritional 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 IIIstudies ofcombined androgen blockade(nilutamide +orchiectomy) in men withadvanced prostate cancer.b= Incidence ≥5% regardless ofcausality.Sources:See template.
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
Hemicandlymphatic system Anemia 7.2 6.4
Metabolicandnutritional 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
Skinandappendages 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 IIIstudies ofcombined androgen blockade(nilutamide +GnRH agonist) in men withadvanced prostate cancer.b= Incidence ≥5% regardless ofcausality.Sources:See template.

Pharmacology

[edit]

Pharmacodynamics

[edit]

Antiandrogenic activity

[edit]
Affinities[a][68]
Compound RBATooltip 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:
  1. ^At androgen receptors; measured in human prostate tissue.
  2. ^Relative toMetribolone,which is by definition 100%

Nilutamide acts as aselectivecompetitivesilent antagonistof 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 ofbicalutamideand2-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,andprolactinlevels due to inhibition of AR-mediated suppression ofsteroidogenesisvianegative feedbackon 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 asleuprorelinin 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 barrierand hascentralantiandrogen actions.[30]

Relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor
Species IC50Tooltip Half maximal inhibitory concentration(nM) RBATooltip Relative binding affinity(ratio)
Bicalutamide 2-Hydroxyflutamide Nilutamide Bica/2-OH-flu Bica/nilu Ref
Rat 190 700 ND 4.0 ND [73]
Rat ~400 ~900 ~900 2.3 2.3 [74]
Rat ND ND ND 3.3 ND [75]
Rata 3595 4565 18620 1.3 5.2 [76]
Human ~300 ~700 ~500 2.5 1.6 [77]
Human ~100 ~300 ND ~3.0 ND [78]
Humana 2490 2345 5300 1.0 2.1 [76]
Footnotes:a= Controversial data.Sources:See template.

Cytochrome P450 inhibition

[edit]

Nilutamide is known to inhibit severalcytochrome P450enzymes, includingCYP1A2,CYP2C9,andCYP3A4,and can result in increased levels of medications that aremetabolizedby theseenzymes.[79]It has also been found to inhibit the enzymeCYP17A1(17α-hydroxylase/17,20-lyase)in vitroand thus thebiosynthesisof androgens.[80][81]However, nilutamide monotherapy significantly increases testosterone levelsin vivo,so the clinical significance of this finding is uncertain.[80][81]

Pharmacokinetics

[edit]

Nilutamide has anelimination half-lifeof 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 ismetabolizedbyCYP2C19,with at least fivemetabolites.[5]Virtually all of the antiandrogenic activity of nilutamide comes from the parent drug (as opposed to metabolites).[83]

Chemistry

[edit]

Nilutamide is structurally related to thefirst-generationNSAAsflutamideandbicalutamideas well as to thesecond-generationNSAAsenzalutamideandapalutamide.

History

[edit]

Nilutamide was developed byRousseland 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]

Society and culture

[edit]

Generic names

[edit]

Nilutamideis thegeneric nameof the drug and itsINNTooltip International Nonproprietary Name,USANTooltip United States Adopted Name,BANTooltip British Approved Name,andDCFTooltip Dénomination Commune Française.[9][10][11][12]

Brand names

[edit]

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

Availability

[edit]

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]

Research

[edit]

The combination of anestrogenand nilutamide as a form ofcombined androgen blockadefor the treatment of prostate cancer has been studied in animals.[86]

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

References

[edit]
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  50. ^Deepinder F, Braunstein GD (September 2012). "Drug-induced gynecomastia: an evidence-based review".Expert Opinion on Drug Safety.11(5): 779–795.doi:10.1517/14740338.2012.712109.PMID22862307.S2CID22938364.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 [...]
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  64. ^Chitturi S, Farrell GC (2013). "Adverse Effects of Hormones and Hormone Antagonists on the Liver".Drug-Induced Liver Disease.Vol. 3. pp. 605–619.doi:10.1016/B978-0-12-387817-5.00033-9.ISBN9780123878175.PMID11096606.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

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