|Trade names||Nilandron, Anandron|
|ATC code||L02BB02 (WHO)|
|Metabolism||Liver: CYP2C19, FMO|
|Metabolites||At least 5, some active|
|Biological half-life||23–87 hours (mean 56 hours, or about 2 days)|
|Chemical and physical data|
|Molar mass||317.221 g/mol|
|3D model (Jmol)||Interactive image|
Nilutamide (brand names Nilandron (US), Anandron (CA)) is a synthetic, non-steroidal antiandrogen (NSAA) used in the treatment of advanced-stage (metastatic) prostate cancer. It was developed by Roussel, first introduced in 1987 (in Europe) 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. Because most prostate cancer cells rely on activation of the androgen receptor (AR) for growth and survival, nilutamide can slow the progression of the disease and extend life in men with prostate cancer.
Nilutamide shows unique and unfavorable tolerability and toxicity profiles, most importantly a high incidence of interstitial pneumonitis (which can progress to pulmonary fibrosis, a potentially fatal condition), and this has limited its clinical use. From a safety standpoint, bicalutamide is clinically preferred not only over nilutamide (due primarily to its risk of interstitial pneumonitis) but also flutamide (due to its high risk of hepatotoxicity) in choice of NSAA.
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.
Transgender hormone therapy
Nilutamide has been researched and used as a component of hormone replacement therapy in transgender women. It has been assessed in at least five small clinical studies for this purpose in treatment-naive subjects. 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, including breast development, decreased body hair (though not facial hair), decreased morning erections and sex drive, and positive psychological and emotional changes. Signs of breast development occurred in all subjects within 6 weeks and were associated with increased nipple sensitivity, and along with decreased hair growth, were the earliest sign of feminization.
Nilutamide did not change the size of the prostate gland (which is the same as with high-dosage cyproterone acetate and ethinyl estradiol 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. In addition, readily apparent histological changes were observed in the testes, including a reduction in tubular and interstitial cells.
Nilutamide was found to more than double luteinizing hormone (LH) and testosterone levels and to triple estradiol levels. In contrast, follicle-stimulating hormone levels remained unchanged. A slight but significant increase in prolactin levels was observed, and levels of sex hormone-binding globulin increased as well. The addition of ethinyl estradiol to nilutamide therapy after 8 weeks abolished the increase in LH, testosterone, and estradiol levels and dramatically suppressed testosterone levels, into the castrate range. 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.
Tolerability and safety
General side effects of NSAAs, including nilutamide, include gynecomastia (40–80%), 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. Also, nausea (24–27%), vomiting, constipation (20%), and insomnia (16%) may occur with nilutamide.
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, a disulfiram-like alcohol intolerance (19%), interstitial pneumonitis (0.77–2.4%) (which can result in dyspnea (1%) as a secondary effect and can progress to pulmonary fibrosis), and hepatitis (1%), and has a higher incidence of nausea and vomiting compared to other NSAAs. 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. There is a case report of simultaneous liver and lung toxicity in a nilutamide-treated patient.
There is also a risk of hepatoxicity with nilutamide, though occurrence is very rare and the risk is significantly less than with flutamide. The incidence of abnormal liver function tests (e.g., elevated liver enzymes) is 2–3% with nilutamide, relative to 42–62% for flutamide. Fulminant hepatic failure has been reported for nilutamide, with fatal outcome. 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. The nitro group of nilutamide has been theorized to be involved in both its hepatotoxicity and its pulmonary toxicity.
Nilutamide acts as a selective competitive silent antagonist of the androgen receptor (AR) (IC50 = 412 nM), which prevents testosterone and other androgens from activating the AR. 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.
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. 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).
Cytochrome P450 inhibitor
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 a half-life of 23–87 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).
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