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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
  • US: WARNING[3]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityGood[2]
Protein binding80–84%[4]
MetabolismLiver (CYP2C19, FMOTooltip flavin-containing monooxygenase)[2][4]
MetabolitesAt least 5, some active[4][5]
Elimination half-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
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.153.268 Edit this at Wikidata
Chemical and physical data
FormulaC12H10F3N3O4
Molar mass317.224 g·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-N checkY
  (verify)

Nilutamide, sold under the brand names Nilandron and Anandron, is a nonsteroidal antiandrogen (NSAA) which is used in the treatment of prostate cancer.[8][9][10][11][12][13] It has also been studied as a component of feminizing hormone therapy for transgender women and to treat acne and seborrhea in women.[14][15][16][17] It is taken by mouth.[4]

Side effects in men include breast tenderness and enlargement, feminization, sexual dysfunction, and hot flashes.[18][19][20][21] Nausea, vomiting, visual disturbances, alcohol intolerance, elevated liver enzymes, and lung disease can occur in both sexes.[21][22][19][23][24][25] Rarely, nilutamide can cause respiratory failure and liver 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 a selective antagonist of the androgen receptor (AR), preventing the effects of androgens like testosterone and dihydrotestosterone (DHT) in the body.[28][14] 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.[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, namely bicalutamide and enzalutamide, due to their better efficacy, tolerability, and safety, and is now rarely used.[34]

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

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.[27][36] It is not indicated as a monotherapy 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 the testosterone flare at the start of GnRH agonist therapy in men with prostate cancer.[38][39][40]

Transgender hormone therapy

Nilutamide has been studied for use as a component of feminizing hormone therapy for transgender women.[14][15] It has been assessed in at least five small clinical 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 clinical feminization in young transgender women (age range 19–33 years) within 8 weeks,[42] including breast development, decreased body hair (though not facial hair),[41] decreased morning erections and sex 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 increased nipple sensitivity,[45][42][43] and along with decreased hair growth, were the earliest sign of feminization.[42]

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.[44][45][47] In addition, readily apparent histological changes were observed in the testes, including a reduction in tubular and interstitial cells.[44]

Nilutamide was found to more than double luteinizing hormone (LH) and testosterone levels and to triple estradiol levels.[41][42][44] In contrast, follicle-stimulating hormone levels remained unchanged.[42][44] A slight but significant increase in prolactin levels was observed, and levels of sex 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 the castrate range.[41][42] 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.[41][42]

Skin conditions

Nilutamide has been assessed in the treatment of acne and seborrhea 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]

Available forms

Nilutamide is available in the form of 50 and 150 mg oral tablets.[48]

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.[19][20][21] Also, nausea (24–27%), vomiting, constipation (20%), and insomnia (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 reversible visual disturbances (31–58%) including delayed ocular adaptation to darkness and impaired color vision,[22] a disulfiram-like[19] alcohol intolerance (19%), interstitial pneumonitis (0.77–2.4%)[34][53][54] (which can result in dyspnea (1%) as a secondary effect and can progress to pulmonary fibrosis),[23] and hepatitis (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 in Japanese patients (12.6%), warranting particular caution in Asian 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 of hepatotoxicity with nilutamide, though occurrence is very rare and the risk is significantly less than with flutamide.[6][59] The incidence of abnormal liver 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 of flutamide.[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 for cyproterone acetate, 4 for nilutamide, and 1 for bicalutamide.[64] 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.[63][65][66] The nitro group of nilutamide has been theorized to be involved in both its hepatotoxicity and its pulmonary 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
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.
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

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 to Metribolone, which is by definition 100%

Nilutamide acts as a selective competitive silent 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 of bicalutamide and 2-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 inhibit 5α-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, and prolactin levels due to inhibition of AR-mediated suppression of steroidogenesis via negative feedback on the hypothalamic–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 as leuprorelin in prostate cancer to suppress androgen concentrations to castrate levels in order to attain maximal androgen blockade (MAB).[14]

Like flutamide and bicalutamide, nilutamide is able to cross the blood–brain barrier and has central antiandrogen actions.[73]

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 [74]
Rat ~400 ~900 ~900 2.3 2.3 [75]
Rat ND ND ND 3.3 ND [76]
Rata 3595 4565 18620 1.3 5.2 [77]
Human ~300 ~700 ~500 2.5 1.6 [78]
Human ~100 ~300 ND ~3.0 ND [79]
Humana 2490 2345 5300 1.0 2.1 [77]
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.[80] It has also been found to inhibit the enzyme CYP17A1 (17α-hydroxylase/17,20-lyase) in vitro and thus the biosynthesis of androgens.[81][82] However, nilutamide monotherapy significantly increases testosterone levels in vivo, so the clinical significance of this finding is uncertain.[81][82]

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.[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).[83] 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).[84]

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.[9][29][30] It was first introduced for medical use in 1987 in France[6][85] and was the second NSAA to be marketed, with flutamide preceding it and bicalutamide following it in 1995.[13][86] It was not introduced until 1996 in the United States.[31][32][33]

Society and culture

Generic names

Nilutamide is the generic name of the drug and its INNTooltip International Nonproprietary Name, USANTooltip United States Adopted Name, BANTooltip British Approved Name, and DCFTooltip Dénomination Commune Française.[9][10][11][12]

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.[10][12]

Availability

Nilutamide is or has been available in the United States, Canada, Australia, Europe, Latin America, Egypt, and Lebanon.[10][12] 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.[10][12] in Latin America, it is or has been available in Argentina, Brazil, and Mexico.[10][12]

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.[87]

Nilutamide has been studied in the treatment of advanced breast cancer.[88][89]

References

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  2. ^ a b c d e Michael C. Perry; Donald C. Doll; Carl E. Freter (30 July 2012). Perry's The Chemotherapy Source Book. Lippincott Williams & Wilkins. pp. 711–. ISBN 978-1-4698-0343-2.
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  47. ^ 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).
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  63. ^ a b Merwat, 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. ISSN 0163-2116. PMID 18688719. S2CID 27421870. 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].
  64. ^ Chitturi, Shivakumar; Farrell, Geoffrey C (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. 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

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