Nilutamide

Publisher Website
Google Scholar
Abstract
Nilutamide is a nonsteroidal antiandrogen with affinity for androgen receptors but not for progestogen, estrogen, or glucocorticoid receptors. Consequently, nilutamide blocks the action of androgens of adrenal and testicular origin which stimulate the growth of normal and cancerous prostatic tissue. Nilutamide has a long half life which permits once-daily administration. Nilutamide is usually given in combination with surgical or chemical castration using gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LHRH)] agonists. In castrated patients the addition of nilutamide improves objective response rates, bone pain, urinary symptoms, tumour markers and time to disease progression. The tolerance of nilutamide is generally acceptable. Adverse effects are usually mild and reversible and consistent with androgen depletion. Unexpected but reversible adverse effects of nilutamide include delayed adaption to dark after exposure to bright light, transient increases in transaminases, and more severe but rare interstitial pneumonitis. Thus, nilutamide is a welcome treatment option that may be particularly useful in patients to whom the convenience of once-daily administration is seen as a worthwhile benefit. Nilutamide is a nonsteroidal antiandrogen with weak affinity for androgen receptors. It is considered a ‘pure’ antiandrogen since it has limited affinity for progestogen and glucocorticoid receptors. Although nilutamide binds only weakly to androgen receptors in vitro, it produces sustained receptor antagonism in vivo. Evidence suggests that nilutamide inhibits the synthesis of androgens, in particular those of adrenal origin, in addition to its effects at the androgen receptor. Importantly, it does not impair the synthesis of glucocorticoids. Binding of nilutamide to androgen receptors in the pituitary prevents the negative feedback effect of testosterone, increasing luteinising hormone release which, theoretically, stimulates further testosterone secretion. However, in humans testosterone levels plateau after a 2-fold increase. Further, this effect can be blocked by concomitant administration of a GnRH agonist. In castrated mice inoculated with various androgen-dependent tumour cell lines, nilutamide reduces the incidence and development of tumours. In contrast, nilutamide, flutamide and cyproterone acetate stimulate androgen-dependent processes in specific androgen-dependent tumour cell models. In rats, prostate weight decreases to a greater extent after combination treatment with nilutamide and a GnRH agonist than after a GnRH agonist alone. In human subjects undergoing gender transformation, it appears that nilutamide does not change prostate volume. Nilutamide is fully absorbed after oral administration, with peak plasma concentrations of 0.9 mg/L occurring within 3 hours of a single dose (150 or 200mg) in patients with prostate cancer. Mean plasma elimination half-life in patients with prostate cancer is 56 hours, suggesting that the drug can be given as a single daily dose, and steady-state plasma concentrations (4.4 to 8.5 mg/L according to the dose) are achieved within approximately 2 weeks. Nilutamide is extensively metabolised, with one of the metabolites interacting with androgen receptors and the prostate of castrated rats, although its activity is much less than that of the parent compound. Plasma clearance of nilutamide appears to decrease with repeated administration. Placebo-controlled studies in orchiectomised patients with stage D (metastatic) prostate cancer have shown that nilutamide (150 or 300 mg/day) is significantly more effective than placebo in terms of objective responses. Subjective responses (based on bone pain relief and performance status) have also been observed in more nilutamide than placebo recipients. Although time to progression was significantly increased, so far there has been no significant difference in favour of nilutamide in improving survival, but only trends. Nilutamide has also been compared with placebo in patients receiving the GnRH agonist buserelin, and has been shown to be effective in preventing the ‘disease flare’ associated with the initial increase in testosterone levels observed at the beginning of GnRH agonist therapy. Placebo-controlled studies have shown a significantly better objective response rate, improvement of bone pain and normalisation of tumour markers with a GnRH agonist plus nilutamide than with a GnRH agonist alone. Nilutamide has been assessed as monotherapy only in a small number of previously untreated patients; an objective partial response rate of 38.5% was achieved. Nilutamide has been relatively well tolerated in clinical trials. Nilutamide 150 to 300 mg/day produces a delayed adaptation to darkness in about 30% of patients. This is reversible on discontinuation of therapy, or perhaps even spontaneously. Hepatotoxicity and interstitial pneumonitis are rare but serious adverse events that have been reported in patients receiving nilutamide. Adverse events related to androgen deprivation, such as hot flushes, gynaecomastia and impotence, occur commonly with nilutamide, as they do with most drugs used in the treatment of prostatic cancer. Nausea, vomiting, and alcohol intolerance have commonly been observed during nilutamide treatment. Pruritus, dizziness and headache have been reported rarely. Effects on sexual function are difficult to assess since the drug is recommended to be used in combination with castration. It is possible that nilutamide may interact with drugs metabolised by the cytochrome P-450 system but this has not been observed in clinical practice. Nilutamide is administered orally as a single daily dose of 300mg for 1 month, then 150 mg/day thereafter, in previously untreated patients, in combination with a GnRH agonist or orchiectomy.