Flutamide

Prostate cancer

GnRH is released by the hypothalamus in a pulsatile fashion; this causes the anterior pituitary gland to release luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH stimulates the testes to produce testosterone, which is metabolized to DHT by the enzyme 5α-reductase.

DHT, and to a significantly smaller extent, testosterone, stimulate prostate cancer cells to grow. Therefore, blocking these androgens can provide powerful treatment for prostate cancer, especially metastatic disease. Normally administered are GnRH analogues, such as leuprorelin or cetrorelix. Although GnRH agonists stimulate the same receptors that GnRH does, since they are present continuously and not in a pulsatile manner, they serve to inhibit the pituitary gland and therefore block the whole chain. However, they initially cause a surge in activity; this is not solely a theoretical risk but may cause the cancer to flare. Flutamide was initially used at the beginning of GnRH agonist therapy to block this surge, and it and other NSAAs continue in this use. In contrast to GnRH agonists, GnRH antagonists don't cause an initial androgen surge, and are gradually replacing GnRH agonists in clinical use.

There have been studies to investigate the benefit of adding an antiandrogen to surgical orchiectomy or its continued use with a GnRH analogue (combined androgen blockade (CAB)). Adding antiandrogens to orchiectomy showed no benefit, while a small benefit was shown with adding antiandrogens to GnRH analogues.

Unfortunately, therapies which lower testosterone levels, such as orchiectomy or GnRH analogue administration, also have significant side effects. Compared to these therapies, treatment with antiandrogens exhibits "fewer hot flashes, less of an effect on libido, less muscle wasting, fewer personality changes, and less bone loss." However, antiandrogen therapy alone is less effective than surgery. Nevertheless, given the advanced age of many with prostate cancer, as well as other features, many men may choose antiandrogen therapy alone for a better quality of life.

Hyperandrogenism

Flutamide has been researched and used extensively in the treatment of hyperandrogenism (e.g., in polycystic ovary syndrome) in women and is highly effective in controlling symptoms including acne, seborrhea, hirsutism, and androgenetic alopecia. The dosages employed are lower than those used in the treatment of prostate cancer. Although flutamide continues to be used for this indication, its use in recent years has been limited due to the risk of potentially fatal hepatotoxicity, and it is not recommended as a first-line therapy. The related NSAA bicalutamide has also been found to be highly effective in the treatment of hirsutism in women and has a far lower and only small risk of hepatotoxicity in comparison.

Transgender hormone therapy

Flutamide is used as a component of hormone replacement therapy for trans women. However, its use for this purpose is discouraged due to reports, albeit rare, of hepatotoxicity in prostate cancer patients at comparable doses.

Side effects

The side effects of flutamide are sex-dependent. In men, a variety of side effects related to androgen deprivation may occur, the most common being gynecomastia and breast tenderness The vast majority (>90%) of cases of gynecomastia with non-steroidal antiandrogens including flutamide are mild to moderate. and others including hot flashes, decreased muscle mass, decreased bone mass and an associated increased risk of fractures, depression, and sexual dysfunction including reduced libido and erectile dysfunction. In women, flutamide is, generally, relatively well-tolerated, and does not interfere with ovulation. The only common side effect reported with flutamide in women is dry skin (75%), which is attributable to diminished androgen-mediated sebum production. General side effects that may occur in either sex include dizziness, anorexia, gastrointestinal side effects such as nausea, vomiting, and diarrhea, a greenish-bluish discoloration of the urine, and hepatic changes. Because flutamide is a pure antiandrogen, unlike steroidal antiandrogens like cyproterone acetate and megestrol acetate (which additionally possess progestogenic activity), it does not appear to have a risk of cardiovascular side effects (e.g., thromboembolism) or fluid retention.

Tamoxifen, a selective estrogen receptor modulator with predominantly antiestrogenic actions, can counteract flutamide-induced gynecomastia and breast pain in men.

Diarrhea

Diarrhea is more common and sometimes more severe with flutamide than with other NSAAs. In a comparative trial of combined androgen blockade for prostate cancer, the rate of diarrhea was 26% for flutamide and 12% for bicalutamide. Moreover, 6% of flutamide-treated patients discontinued the drug due to diarrhea, whereas only 0.5% of bicalutamide-treated patients did so. In the case of antiandrogen monotherapy for prostate cancer, the rates of diarrhea are 5–20% for flutamide, 2–5% for bicalutamide, and 2–4% for nilutamide. In contrast to diarrhea, the rates of nausea and vomiting are similar among the three drugs.

Hepatotoxicity

Although rare, flutamide has been associated with severe hepatotoxicity and death. By 1996, 46 cases of severe cholestatic hepatitis had been reported, with 20 fatalities. There have been continued case reports since, including liver transplants and death. Based on the number of prescriptions written, the rate of serious hepatotoxicity associated with flutamide treatment is estimated to be 3 per 10,000. However, other researchers have suggested that the incidence of significant hepatotoxicity may be as high as 6–9%. Another source reported a rate of 0.36%. Flutamide is also associated with liver enzyme elevations in 42–62% of patients. The risk of hepatotoxicity with flutamide treatment is far higher than with nilutamide or bicalutamide. Lower dosages of the drug appear to have a reduced but still significant risk. Liver function should be monitored regularly with liver function tests during flutamide treatment. In addition, due to the high risk of serious hepatotoxicity, flutamide should not be used in the absence of a serious indication.

The mechanism of action of flutamide-induced hepatotoxicity is thought to be due to mitochondrial toxicity. Specifically, flutamide and particularly its major metabolite 2-hydroxyflutamide inhibit enzymes in the mitochondrial electron transport chain in hepatocytes, including respiratory complexes I (NADH ubiquinone oxidoreductase), II (succinate dehydrogenase), and V (ATP synthase), and thereby reduce cellular respiration via ATP depletion and hence decrease cell survival. Inhibition of taurocholate (a bile acid) efflux has also been implicated in flutamide-induced hepatotoxicity. In contrast to flutamide and 2-hydroxyflutamide, which severely compromise hepatocyte cellular respiration in vitro, bicalutamide does not significantly do so at the same concentrations and is regarded as non-mitotoxic. It is thought that the nitroaromatic group of flutamide and 2-hydroxyflutamide enhance their mitochondrial toxicity; bicalutamide, in contrast, possesses a cyano group in place of the nitro moiety, greatly reducing the potential for such toxicity.

The combination of paracetamol (acetaminophen) and flutamide may result in additive to synergistic hepatotoxicity, indicating a potential drug interaction.

Pulmonary toxicity

Flutamide has also been associated with interstitial pneumonitis (which can progress to pulmonary fibrosis). The incidence of interstitial pneumonitis with flutamide was found to be 0.04% in a large clinical cohort of 41,700 prostate cancer patients.

Photosensitivity

A variety of case reports have associated flutamide with photosensitivity.

Comparison with other antiandrogens

Flutamide has been found to be similarly effective in the treatment of prostate cancer to bicalutamide, although indications of superior efficacy, including greater compensatory increases in testosterone levels and greater reductions in PSA levels, were observed with bicalutamide. Flutamide, at a dosage of 750 mg/day (250 mg three times daily), has also been found to be equivalent in effectiveness to 250 mg/day oral cyproterone acetate as a monotherapy in the treatment of prostate cancer in a large-scale clinical trial of 310 patients, though its side effect and toxicity profile (including gynecomastia, diarrhea, nausea, loss of appetite, and liver disturbances) was regarded as considerably worse than that of cyproterone acetate. In contrast to the case of men, flutamide has been found to be significantly more effective than cyproterone acetate (as well as another steroidal antiandrogen, spironolactone) in the treatment of androgen-dependent conditions such as acne and hirsutism in women. This sex difference in effectiveness may be related to the fact that flutamide significantly increases androgen levels in men, which counteracts its antiandrogen efficacy, but does not increase androgen levels in women. (In contrast to flutamide, cyproterone acetate, due to its progestogenic and antigonadotropic activity, does not increase and rather suppresses androgen levels in both sexes.)

Antiandrogen

Flutamide acts as a selective, competitive, silent antagonist of the androgen receptor (AR). Its active metabolite, 2-hydroxyflutamide, has between 10- to 25-fold higher affinity for the AR than does flutamide, and hence is a more powerful antiandrogen in comparison. However, at high concentrations, unlike flutamide, 2-hydroxyflutamide is able to weakly activate the AR. Flutamide has far lower affinity for the AR than do steroidal antiandrogens like spironolactone and cyproterone acetate, and it is a relatively weak antiandrogen in terms of potency by weight, but the large dosages at which flutamide is used appear to compensate for this. In accordance with its selectivity for the AR, flutamide possesses no progestogenic, (direct) estrogenic, glucocorticoid, or antigonadotropic activity. Similarly to nilutamide, bicalutamide, and enzalutamide, flutamide crosses the blood-brain-barrier and exerts central antiandrogen actions.

CYP17A1 inhibitor

Flutamide and 2-hydroxyflutamide have been found in vitro to inhibit CYP17A1 (17α-hydroxylase/17,20-lyase), an enzyme which is required for the biosynthesis of androgens. In accordance, flutamide has been found to slightly but significantly lower androgen levels in GnRH analogue-treated male prostate cancer patients and women with polycystic ovary syndrome. As such, flutamide is a weak inhibitor of androgen biosynthesis. However, the clinical significance of this action may be limited when flutamide is given without a GnRH analogue to non-castrated men, as the drug markedly elevates testosterone levels into the high normal male range via prevention of AR activation-mediated negative feedback on the hypothalamic-pituitary-gonadal axis in this context.

Other actions

In addition to its antiandrogen activity, flutamide has been identified as a putative ligand of the aryl hydrocarbon receptor.

Pharmacokinetics

Flutamide is metabolized by CYP1A2 (via α-hydroxylation) in the liver during first-pass metabolism to its main active form, 2-hydroxyflutamide (which accounts for 23% of an oral dose of flutamide one hour post-ingestion), and to at least five other minor metabolites. Levels of 2-hydroxyflutamide are 50-fold higher than those of flutamide at steady-state. Flutamide is excreted in various forms in the urine, the primary form being 2-amino-5-nitro-4-(trifluoromethyl)phenol.

Flutamide has a fairly short half-life of 5–6 hours. However, the half-life of its active form, 2-hydroxyflutamide, is somewhat longer at about 8–9 hours. In any case, the half-lives of flutamide and 2-hydroxyflutamide are regarded as too short to allow for once-daily dosing, and the drug is instead administered three times daily at 8-hour intervals. In contrast, the newer NSAAs nilutamide, bicalutamide, and enzalutamide all have much longer half-lives, and this allows for once-daily administration in their cases.

Steady-state levels of 2-hydroxyflutamide are achieved after 2–4 days of flutamide administration.

Although 2-hydroxyflutamide has a half-life of 8–9 hours in elderly men, it has been reported to possess a shorter half-life in younger men.

Chemistry

Unlike the hormones with which it competes, flutamide is not a steroid; rather, it is a substituted anilide. Hence, it is described as non-steroidal in order to distinguish it from older steroidal antiandrogens such as cyproterone acetate and megestrol acetate.

History

Flutamide was first synthesized in 1967 by Neri and colleagues at Schering Plough Corporation. It was originally synthesized as a bacteriostatic agent, but was subsequently, and serendipitously found to possess antiandrogen activity. The code name of flutamide during development was SCH-13521. Clinical research of the drug began in 1971, and it was first marketed in 1983. Flutamide was not introduced in the United States until 1989; it was specifically approved by the U.S. Food and Drug Administration for the treatment of metastatic prostate cancer in combination with a gonadotropin-releasing hormone (GnRH) analogue. Flutamide was the first NSAA to be introduced, and was followed by nilutamide in 1989 and then bicalutamide in 1995.

Generic name

Flutamide is the INN, USAN, BAN, DCF, and JAN of the drug. Its names in Latin, German, and Spanish are flutamidum, flutamid, and flutamida, respectively.

Brand names

Brand names of flutamide include or have included Cebatrol, Cytomid, Drogenil, Etaconil, Eulexin, Flucinom, Flumid, Flutacan, Flutamid, Flutamida, Flutamin, Flutan, Flutaplex, Flutasin, Fugerel, Profamid, and Sebatrol, among others.

Availability

Flutamide is marketed widely throughout the world, including in the United States, Canada, Europe, Australia, New Zealand, South Africa, Central and South America, East and Southeast Asia, India, and the Middle East.