|Systematic (IUPAC) name|
|Trade names||Casodex, Cosudex, Calutide, Kalumid|
|Metabolites||Bicalutamide glucoronide, hydroxybicalutamide, hydroxybicalutamide glucuronide (all inactive)|
|Biological half-life||6 days (acute),
7–10 days (chronic)
|Excretion||Feces (43%), urine (34%)|
|ATC code||L02BB03 (WHO)|
|PDB ligand ID||198 (PDBe, RCSB PDB)|
|Molar mass||430.373 g/mol|
|Melting point||191 to 193 °C (376 to 379 °F)|
|Solubility in water||0.005 mg/mL (20 °C)|
|(what is this?)|
Bicalutamide (brand name Casodex) is a synthetic, non-steroidal antiandrogen (NSAA) that is used primarily in the treatment of prostate cancer. It is also used in the treatment of hirsutism and other androgen-dependent conditions and as a component of hormone replacement therapy for transgender women. Bicalutamide acts as a selective antagonist of the androgen receptor (AR), preventing androgens like testosterone and dihydrotestosterone (DHT) from binding to and activating the AR and exerting their biological effects. Developed and marketed by AstraZeneca, the drug was approved in 1995 as a combination treatment (with a gonadotropin-releasing hormone (GnRH) analogue (e.g., leuprorelin) or surgical castration) for stage D2 metastatic prostate cancer. Since then, it has also been approved and used, for instance in Germany (though not in the United States), as a monotherapy for the treatment of an earlier stage of the disease, stage C or D1 locally advanced prostate cancer.
Since their introduction, bicalutamide and the other NSAAs have largely replaced the steroidal antiandrogen cyproterone acetate (CPA) in the treatment of prostate cancer. Bicalutamide was the third NSAA to be marketed, following flutamide and nilutamide. It has substantially reduced toxicity relative to the earlier antiandrogens, and in contrast to them, is said to have an excellent and favorable safety profile. For this reason, as well as superior potency, tolerability, and pharmacokinetics, bicalutamide is preferred and has largely replaced flutamide and nilutamide in clinical practice. Prior to the 2012 approval of enzalutamide, a more potent and efficacious NSAA with even greater effectiveness, bicalutamide was the most widely used antiandrogen in the treatment of prostate cancer, and was regarded as the standard-of-care antiandrogen in the treatment of the disease.
- 1 Medical uses
- 2 Side effects
- 3 Contraindications
- 4 Interactions
- 5 Comparison with other antiandrogens
- 6 Pharmacology
- 6.1 Antiandrogen
- 6.2 Other actions
- 7 Pharmacokinetics
- 8 Chemistry
- 9 History
- 10 Society and culture
- 11 Research
- 12 References
- 13 Further reading
- 14 External links
Bicalutamide is indicated as a means of androgen deprivation therapy for the treatment of stage D2 metastatic prostate cancer in combination with castration (pharmacological with a GnRH analogue or surgical with an orchiectomy) or at a higher dosage as a monotherapy. It has not been found to be effective as a monotherapy in prostate cancer at the same dosage as that in which it is approved in combination with a GnRH analogue.
While effective initially, most advanced prostate cancer patients eventually become resistant to antiandrogen including bicalutamide therapy due to progressive mutations in the AR, resulting in the transformation of these drugs from antagonists into agonists of the AR.
Excess hair and acne
Low-dose bicalutamide has been found to be effective in the treatment of hirsutism in women. The drug was well-tolerated, all of the patients experienced a visible decrease in hair density, and a highly significant clinical improvement was observed with the Ferriman–Gallwey score decreasing by 41.2% at three months and by 61.6% at six months. According to Oner et al., "Low dose bicalutamide (25 mg/day) was shown to be effective in the treatment of hirsutism related to [idiopathic hirsutism] and [polycystic ovary syndrome]. It does not have any significant side effects [or] lead to irregular periods. [...] Since all [antiandrogens] are teratogenic, contraception should absolutely be recommended to patients."
In addition to hirsutism, bicalutamide can also be used in the treatment of acne in women. Several studies have observed complete clearing of acne with flutamide in women, and similar or benefits would be expected with bicalutamide.:712–717 Bicalutamide may also treat other androgen-dependent skin conditions, such as seborrhea and androgenic alopecia. Flutamide has been found to produce a decrease of hirsutism score to normal and an 80% or greater decrease in scores of acne, seborrhea, and androgen-dependent hair loss. Moreover, in combination with an oral contraceptive, flutamide treatment resulted in an increase in cosmetically acceptable scalp hair density in 6 of 7 women suffering from androgenic alopecia.
Transgender hormone therapy
Bicalutamide is used as a component of hormone replacement therapy in the treatment of transgender women. Beneficial or desired effects include breast development, decreased muscle mass, reduced male-pattern hair, lowered libido, and loss of spontaneous erections. Bicalutamide increases estradiol levels in biological males and hence has indirect estrogenic properties in this population. This is an action that can be considered to be desirable in transgender women, as it results in or contributes to feminization.
Male early puberty
Bicalutamide is useful in combination with the aromatase inhibitor anastrozole as a puberty blocker in the treatment of male precocious puberty. This is potentially a cost-effective alternative to GnRH analogues for the treatment of this condition, as GnRH analogues are very expensive. Moreover, the combination is effective in gonadotropin-independent precocious puberty, namely familial male-limited precocious puberty (also known as testotoxicosis), where GnRH analogues notably are not effective. Bicalutamide has been found to be superior to the steroidal antiandrogen spironolactone (which is also used, in combination with the aromatase inhibitor testolactone) for this indication; it has shown greater effectiveness and possesses fewer side effects in comparison.
The side effect profile of bicalutamide is highly sex-dependent. In women, the side effects of pure antiandrogens/NSAAs are minimal, and bicalutamide has been found to be very well-tolerated. In men however, due to androgen deprivation, a variety of side effects of varying severity may occur during bicalutamide treatment, with breast pain/tenderness and gynecomastia (70–80%) being the most common and others including physical feminization and demasculinization in general (e.g., decreased muscle mass and strength and reduced body hair growth and density), hot flashes, fatigue, weakness, depression, sexual dysfunction (including loss of libido and erectile dysfunction), and decreased bone density and a resultant increased risk of fractures. In addition, reduction of the weight of the prostate gland and seminal vesicles (though not of the testes) and, consequently, reversible hypospermia or aspermia (reduced or absent semen/ejaculate production) may occur. However, in contrast, bicalutamide does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish the capacity/potential for fertility. General side effects of bicalutamide that may occur in either sex include diarrhea, nausea, dry skin, and itching.
Bicalutamide is well-tolerated at higher dosages (than the 50 mg/day dosage) with rare additional side effects.
Combination of bicalutamide with medical (i.e., a GnRH analogue) or surgical castration modifies the side effect profile of the drug. Some of its side effects, including breast pain/tenderness and gynecomastia, are far less likely to occur when the drug is combined with a GnRH analogue, while certain other side effects, including hot flashes, depression, fatigue, and sexual dysfunction, occur much more frequently in combination with a GnRH analogue. It is thought that this is due to the suppression of estrogen levels (in addition to androgen levels) by GnRH analogues, as estrogen may compensate for various negative central effects of androgen deprivation. If bicalutamide is combined with a GnRH analogue or surgical castration, the elevation of androgen and estrogen levels in men caused by bicalutamide will be prevented and the side effects of excessive estrogens, namely gynecomastia, will be reduced. However, due to the loss of estrogen, bone loss will accelerate and the risk of osteoporosis developing with long-term therapy will increase.
In the case that bicalutamide is used as a monotherapy (and thus is not combined with a GnRH analogue), tamoxifen, a selective estrogen receptor modulator with antiestrogenic actions in breast tissue and estrogenic actions in bone, has been found to be effective in preventing and reversing bicalutamide-induced gynecomastia in men. Moreover, in contrast to GnRH analogues, tamoxifen poses minimal risk of accelerated bone loss and osteoporosis. For reasons that are unclear, anastrozole, an aromatase inhibitor (inhibitor of estrogen biosynthesis), has been found to be much less effective in comparison to tamoxifen for treating bicalutamide-induced gynecomastia. A systematic review of NSAA-induced gynecomastia and breast tenderness concluded that tamoxifen (10–20 mg/day) and radiotherapy could effectively manage the side effect without relevant adverse effects, though with tamoxifen showing superior effectiveness.
Bicalutamide may cause liver changes rarely, such as elevated transaminases (a marker of hepatotoxicity) and jaundice. In a study of 4,052 prostate cancer patients who received 150 mg/day bicalutamide as a monotherapy, the incidence of abnormal liver function tests was 3.4% for bicalutamide and 1.9% for standard care (a 1.5% difference attributable to bicalutamide). For comparison, the incidences of abnormal liver function tests are 42–62% for flutamide, 2–3% for nilutamide, and (dose-dependently) between 9.6% and 28.2% for CPA. In contrast, there appears to be no risk with enzalutamide. The risk of liver changes with bicalutamide is considered to be small, but significant, and it is recommended that liver function be periodically monitored. Elevation of transaminases above twice the normal range may be an indication that bicalutamide should be discontinued.
From a theoretical standpoint (on the basis of structure-activity relationships), flutamide, bicalutamide, and nilutamide, to varying extents, are all thought to have the potential to cause liver toxicity. However, relative to flutamide (which has an estimated incidence rate of 3 in every 10,000), hepatotoxicity is far rarer with bicalutamide and nilutamide, with bicalutamide regarded as having the lowest risk. Out of millions of patient exposures, a total of five cases of bicalutamide-associated hepatotoxicity, two of which were fatal, have been reported in the medical literature. One of these cases occurred after only two doses of bicalutamide and may have actually been caused by prolonged prior exposure to flutamide and CPA.
Several case reports of interstitial pneumonitis (which may progress to pulmonary fibrosis) in association with bicalutamide treatment have been published in the medical literature. The risk is considered to be very low, and far less relative to that seen with nilutamide (which has an incidence rate of 0.5–2% of patients).:81 In a large cohort of prostate cancer patients, the incidence of interstitial pneumonitis with NSAAs was highest for nilutamide (0.77%) and much lower for flutamide (0.04%) and bicalutamide (0.01%). In addition to interstitial pneumonitis, a single case report of eosinophilic lung disease in association with six months of 200 mg/day bicalutamide treatment exists. Side effects associated with these rare potential pulmonary adverse reactions of bicalutamide may include dyspnea (difficult breathing or shortness of breath), cough, and pharyngitis (inflammation of the pharynx, resulting in sore throat).
Because bicalutamide blocks the AR, like all antiandrogens, it can interfere with the androgen-mediated sexual differentiation of the genitalia (and brain) during prenatal development. As such, bicalutamide is a teratogen, and may have the potential to produce undervirilization/sexually ambiguous genitalia in male fetuses. For this reason, bicalutamide is contraindicated in women during pregnancy, and women who are sexually active and who can or may become pregnant are strongly recommended to take bicalutamide only in combination with contraception.
In individuals with severe, though not mild-to-moderate hepatic impairment, there is evidence that the elimination of bicalutamide is slowed, and hence, caution should be observed in these patients. In severe hepatic impairment, the half-life of the active R-enantiomer of bicalutamide is increased by 76% (half-life of 5.9 and 10.4 days for normal and impaired patients, respectively). The half-life of bicalutamide is unchanged in renal impairment.
Bicalutamide is almost exclusively metabolized by the enzyme CYP3A4. As such, its levels in the body may be altered by inhibitors and inducers of CYP3A4. Examples of CYP3A4 inhibitors include amiodarone, antiretrovirals, protease inhibitors, cimetidine, clarithromycin, dalfopristin, quinupristin, delavirdine, efavirenz, erythromycin, fluoxetine, fluvoxamine, imatinib, mifepristone, nefazodone, certain azole antifungals, and grapefruit juice, and examples of CYP3A4 inducers include barbiturates, bosentan, carbamazepine, dexamethasone, nevirapine, oxcarbazepine, phenytoin, rifabutin, rifampin, rifapentine, and St. John's Wort.
Comparison with other antiandrogens
Flutamide and nilutamide
Relative to the other first-generation NSAAs, flutamide and nilutamide, bicalutamide has the highest affinity for the AR, as well as the longest half-life (~6 days for bicalutamide versus 5–6 hours for flutamide and ~2 days for nilutamide). It has 4-fold greater affinity for the AR than does 2-hydroxyflutamide, the active metabolite of flutamide (a prodrug). In accordance, the efficacy of bicalutamide has been found to be at least equivalent to flutamide in the treatment of prostate cancer in a direct head-to-head comparison, and indications of superior efficacy, including significantly greater relative decreases and increases in levels of prostate-specific antigen and testosterone, respectively, were observed. The greater AR affinity and longer half-life of bicalutamide allow it to be used at relatively low dosages in comparison to flutamide and nilutamide. As such, bicalutamide is the most potent of the three drugs, and is also the safest and best-tolerated. It is for these reasons that it has largely replaced flutamide and nilutamide in clinical use.
In comparison to bicaclutamide, the newer NSAA enzalutamide has 5- to 8-fold higher affinity for the AR (IC50 of 21 nM or 36 nM for enzalutamide and 160 nM or 159 nM for bicalutamide at the AR), possesses mechanistic differences resulting in improved AR deactivation, shows increased (though by no means complete) resistance to AR mutations in prostate cancer cells causing a switch from antagonist to agonist activity, and has an even longer half-life (8–9 days versus ~6 days for bicalutamide). In accordance, enzalutamide, at a dosage of 160 mg/day, has been found to produce similar increases in testosterone, estradiol, and luteinizing hormone (LH) levels relative to high-dosage bicalutamide (300 mg/day), and an almost two-fold higher increase in testosterone levels relative to 150 mg/day bicalutamide (114% versus 66%). These findings suggest that enzalutamide is a significantly more potent and effective antiandrogen in comparison. Moreover, the drug has demonstrated superior clinical effectiveness in the treatment of prostate cancer in a direct head-to-head comparison with bicalutamide.
Tolerability and safety
In terms of tolerability, enzalutamide and bicalutamide appear comparable in most regards, with a similar moderate negative effect on sexual function and activity for instance. However, enzalutamide has a risk of seizures and other central side effects such as anxiety and insomnia related to off-target GABAA receptor inhibition that bicalutamide does not appear to have. On the other hand, unlike with all of the earlier NSAAs (flutamide, nilutamide, and bicalutamide), there has been no evidence of hepatotoxicity or elevated liver enzymes in association with enzalutamide treatment in clinical trials.
Unlike bicalutamide, enzalutamide is still on-patent, and for this reason, is extremely expensive ($7,450 USD for a 30-day supply as of 2015). In contrast, bicalutamide is off-patent and available as a generic drug, and its cost is very low in comparison (from $15.44 for a 30-day supply of once-daily 50 mg tablets).
CPA and spironolactone
In a large-scale clinical trial that compared 750 mg/day flutamide and 250 mg/day CPA monotherapies in the treatment of men with prostate cancer, the two drugs were found to have equivalent effectiveness on all endpoints. In addition, contrarily to the case of men, flutamide has been found in various clinical studies to be more effective than CPA (and spironolactone) in the treatment of androgen-dependent conditions such as acne and hirsutism in women. This difference in effectiveness in men and women may be related to the fact that NSAAs like flutamide significantly increase androgen levels in men, which counteracts their antiandrogen efficacy, but do not increase androgen levels in women. (In contrast to NSAAs, CPA, due to its progestogenic and hence antigonadotropic activity, does not increase and rather suppresses androgen levels in both sexes.)
Bicalutamide has been found to be at least as effective as flutamide in the treatment of prostate cancer, and markers of superior antiandrogen efficacy, including significantly greater compensatory increases in testosterone levels and reductions in PSA levels, were observed with bicalutamide. In accordance, bicalutamide has the highest affinity for the AR, greatest potency, and longest half-life of the first-generation NSAAs (i.e., flutamide, nilutamide, and bicalutamide), and for these reasons, is considered to be the most powerful antiandrogen of the three. As such, although bicalutamide has not been compared head-to-head to CPA or spironolactone in the treatment of androgen-dependent conditions, flutamide has been found to be either equivalent or more effective than them in clinical studies, and the same would consequently be expected of bicalutamide. Accordingly, a study comparing the efficacy of 50 mg/day bicalutamide versus 300 mg/day CPA in preventing the prostate-specific antigen flare at the start of GnRH agonist therapy in men with prostate cancer found that the two regimens were equivalently effective. There was evidence of a slight advantage in terms of speed of onset and magnitude for the CPA group, but the differences were small and did not reach statistical significance. The differences may have been related to the antigonadotropic activity of CPA (which would directly counteract the GnRH agonist-induced increase in gonadal androgen production) and/or the fact that bicalutamide requires one month to 12 weeks of administration to reach steady-state (maximal) levels.
Tolerability and safety
Bicalutamide is considered to have a superior tolerability profile compared to CPA (due largely to its lack of progestogenic, antigonadotropic, and glucocorticoid activity), and also has a far smaller risk of hepatotoxicity. In addition, unlike spironolactone, bicalutamide has no antimineralocorticoid activity, and for this reason, has no risk of hyperkalemia (which can be life-threatening in severe cases) or other antimineralocorticoid side effects such as urinary frequency, dehydration, hypotension, hyponatremia, metabolic acidosis, or decreased renal function that may occur with spironolactone treatment.
GnRH analogues and castration
Bicalutamide monotherapy has overall been found to be equivalent in effectiveness compared to GnRH analogues and castration in the treatment of prostate cancer. There appears to be a slight effectives advantage for GnRH analogues/castration, but overall, the differences trend towards but do not reach statistical significance.
Monotherapy with NSAAs including bicalutamide, flutamide, nilutamide, and enzalutamide shows a significantly lower risk of certain side effects, including hot flashes, depression, fatigue, loss of libido, and decreased sexual activity, relative to treatment with GnRH analogues, maximal androgen blockade (NSAA and GnRH analogue combination), CPA, or surgical castration in prostate cancer. For example, 60% of men reported complete loss of libido with bicalutamide relative to 85% for maximal androgen blockade and 69% reported complete loss of erectile function relative to 93% for maximal androgen blockade. Another large study reported a rate of impotence of only 9.3% with bicalutamide relative to 6.5% for standard care (the controls), a rate of decreased libido of only 3.6% with bicalutamide relative to 1.2% for standard care, and a rate of 9.2% with bicalutamide for hot flashes relative to 5.4% for standard care. One other study reported decreased libido, impotence, and hot flashes in only 3.8%, 16.9%, and 3.1% of bicalutamide-treated patients, respectively, relative to 1.3%, 7.1%, and 3.6% for placebo. It has been proposed that due to the lower relative effect of NSAAs on sexual interest and activity, with two-thirds of advanced or metastatic prostate cancer patients treated with them retaining sexual interest, these drugs may result in improved quality of life and thus be preferable for those who wish to retain sexual interest and function relative to other antiandrogen therapies in prostate cancer.
Bicalutamide is far less expensive than GnRH analogues, which, in spite of some having been off-patent many years, have been reported (in 2013) to typically cost $10,000 to $15,000 USD per year (or about $1,000 per month) of treatment.
Bicalutamide acts as a highly selective competitive silent antagonist of the AR (IC50 = 190 nM or 243 nM (according to different sources)). Although the affinity of bicalutamide for the AR is approximately 50 times lower than that of DHT (IC50 = 3.8 nM), the main endogenous ligand of the receptor in the prostate gland, sufficient concentrations of bicalutamide efficiently prevent activation of the AR by androgens including testosterone and DHT and subsequent upregulation of the transcription of androgen-responsive genes. The drug has also been found to accelerate the degradation of the AR. The activity of bicalutamide lies in the R-isomer, which binds to the AR with an affinity that is about 30-fold higher than that of the S-isomer. The active R-isomer also has a much longer half-life than the S-isomer, and serum levels of (R)-bicalutamide are about 100-fold greater than those of (S)-bicalutamide at steady state.
Owing to its selectivity, unlike steroidal antiandrogens such as CPA and megestrol acetate, bicalutamide has no additional, off-target hormonal activity (e.g., progestogenic, glucocorticoid, or antimineralocorticoid). However, it does significantly increase estrogen levels secondary to blockade of the AR in males, and for this reason, has some indirect estrogenic effects in men. As an antiandrogen, bicalutamide neither inhibits nor suppresses androgen production in the body (i.e., it does not act as an antigonadotropin) – instead, it exclusively mediates its antiandrogen effects by blocking androgen binding and subsequent receptor activation at the level of the AR.
Based on animal research, it was initially thought that bicalutamide was unable to cross the blood-brain-barrier and hence was a peripherally-selective antiandrogen. This conclusion was drawn from the finding that bicalutamide does not increase LH or testosterone levels in animals (including in rats and dogs), as antiandrogens like flutamide normally do this by blocking ARs in the hypothalamus and pituitary gland and thereby disinhibiting the hypothalamic-pituitary-gonadal (HPG) axis. In humans however, bicalutamide has been found to increase LH and testosterone levels, and to a comparative extent relative to flutamide and nilutamide. As such, it appears that bicalutamide does indeed cross the blood-brain-barrier in humans and affect central function, as supported by potential side effects such as diminished sexual interest, fatigue, and depression in men. It has been stated that this difference of bicalutamide in animals and humans may be due to species-related differences in drug tissue distribution.
Influences on hormone levels
In men, blockade of the AR by bicalutamide in the hypothalamus and pituitary gland suppresses the negative feedback of androgens on the release of LH, resulting in an elevation in LH levels. Follicle-stimulating hormone (FSH) levels, in contrast, remain essentially unchanged. The increase in LH levels leads to a significant increase in androgen and estrogen levels, by up to two-fold in the case of the former. Bicalutamide will more than block the effects of the increased androgen levels (monotherapy is still clinically effective in the treatment of prostate cancer, for instance), but the effects of the elevated estrogen levels will remain unopposed, and are responsible for the feminizing side effects the drug in males, most notably gynecomastia. It is noteworthy that bicalutamide increases androgen and estrogen levels only in men and not in women; this is because androgen levels are far lower in women in comparison and in turn exert little to no basal suppression of the HPG axis. Dosages of bicalutamide of 10 mg, 30 mg, and 50 mg per day have been found to produce a moderate effect on sex hormone levels in men with prostate cancer, providing indication that the drug has clinically-relevant antiandrogen effects at a dosage as low as 10 mg/day.
Differences from castration
It has been proposed that the increase in estrogen levels caused by NSAAs like bicalutamide compensates for androgen blockade in the brain, which may explain differences in the side effect profiles of these drugs relative to GnRH analogues/castration, maximal androgen blockade, and CPA (which, in contrast, decrease both androgen and estrogen levels). In the case of sexual interest and function, this notion is supported by a variety of findings including animal studies showing that estrogen deficiency results in diminished sexual behavior, treatment with tamoxifen resulting in significantly lowered libido in 30% of men receiving it for male breast cancer, and estrogen administration restoring libido and the frequency of sexual intercourse in men with congenital estrogen deficiency, among others.
Several metabolites of testosterone and DHT, including estradiol, 3α-androstanediol, and 3β-androstanediol, are estrogens (mainly potent ERβ agonists in the cases of the latter two), and 3α-androstanediol is also a potent GABAA receptor-potentiating neurosteroid. Due to the fact that bicalutamide does not lower androgen levels, the levels of these metabolites are likely not lowered either, unlike with therapies such as GnRH analogues. (In fact, since bicalutamide actually increases testosterone levels in males, the levels of these metabolites might be elevated similarly.) These steroids have been found to have AR-independent positive effects on sexual motivation, and may explain the preservation of sexual interest and function by bicalutamide and other NSAAs. They also have antidepressant, anxiolytic, and cognitive-enhancing effects, and may account for the lower incidence of depression with bicalutamide and other NSAAs relative to other antiandrogen therapies.
Spermatogenesis and fertility
Unlike with antigonadotropic antiandrogens such as CPA and GnRH analogues, it has been reported that bicalutamide monotherapy (at 50 mg/day) has very little effect on the ultrastructure of the testes and on sperm maturation in humans even after long-term therapy (>4 years). This may be explained by the fact that testosterone levels are far higher in the testes than in the rest of the body (concentrations in the seminiferous tubules (which make up approximately 80% of the bulk of the testes) are 20- to 100-fold greater than circulating levels), and on account of the extremely high levels of androgens that are present, it is likely that systemic bicalutamide therapy is unable to produce intratesticular concentrations of the drug that are able to significantly block androgen action in this part of the body. This is especially so considering that bicalutamide increases circulating testosterone levels, and by extension gonadal testosterone production, by up to two-fold in males. In addition, it is notable that only a fraction (5–10%) of normal intratesticular levels of testosterone (and hence androgen action) is actually necessary to maintain spermatogenesis in human males.
In contrast to bicalutamide and other pure antiandrogens/NSAAs, antigonadotropic antiandrogens suppress gonadotropin secretion, which in turn diminishes testosterone production by the testes as well as the maintenance of the testes by gonadotropins, resulting in atrophy and loss of their function. As such, bicalutamide and other NSAAs may uniquely have the potential to preserve testicular function and spermatogenesis and thus male fertility relative to alternative therapies. In accordance with this notion, a study found that prolonged, high-dose bicalutamide treatment had minimal effects on fertility in male rats. However, another study found that low-dose bicalutamide administration resulted in testicular atrophy and reduced the germ cell count in the testes of male rats by almost 50%, though the rate of successful fertilization and pregnancy following mating was not assessed.
AR activation in prostate cancer
Though a pure, or silent antagonist of the AR under normal circumstances, bicalutamide, as well as other earlier antiandrogens like flutamide and nilutamide, have been found to possess weak partial agonist properties in the setting of AR overexpression and agonist activity in the case of certain mutations in the ligand-binding domain of the AR. As both of these circumstances can eventually occur in prostate cancer, resistance to bicalutamide usually develops and the drug has the potential to paradoxically stimulate tumor growth when this happens. This is the mechanism of the phenomenon of antiandrogen withdrawal syndrome, where antiandrogen discontinuation paradoxically slows the rate of tumor growth. The newer drug enzalutamide has been shown not to have agonistic properties in the context of overexpression of the AR, though certain mutations in the AR can still convert it from an antagonist to agonist.
Cytochrome P450 modulator
It has been reported that bicalutamide may have the potential to inhibit the enzymes CYP3A4 and, to a lesser extent, CYP2C9, CYP2C19, and CYP2D6, based on in vitro research. However, no relevant inhibition of CYP3A4 has been observed in vivo with bicalutamide at a dose of 150 mg (using midazolam as a specific marker of CYP3A4 activity). In animals, bicalutamide has been found to be an inducer of certain cytochrome P450 enzymes. However, dosages of 150 mg/day or less have shown no evidence of this in humans.
Bicalutamide has been identified as a strong CYP27A1 inhibitor in vitro. CYP27A1 converts cholesterol into 27-hydroxycholesterol, an oxysterol that has multiple biological functions including direct, tissue-specific activation of the estrogen receptor (it has been characterized as a selective estrogen receptor) and the liver X receptor. 27-Hydroxycholesterol has been found to increase ER-positive breast cancer cell growth via its estrogenic action, and hence, it has been proposed that bicalutamide and other CYP27A1 inhibitors may be effective as adjuvant therapies to aromatase inhibitors in the treatment of ER-positive breast cancer.
Bicalutamide, as well as enzalutamide, have been found to act as inhibitors of P-glycoprotein (ABCB1) efflux and ATPase activity. This action may reverse docetaxel resistance in prostate cancer cells by reducing transport of the drug out of these cells.
GABAA receptor negative modulator
All of the approved NSAAs, flutamide, nilutamide, bicalutamide, and enzalutamide, have been found to possess an off-target action of inhibiting GABAA receptor currents in vitro to varying extents (IC50 = 7–47 μM for the former three). In addition, flutamide, nilutamide, and enzalutamide have been found to cause convulsions and/or death in mice at sufficient doses. Bicalutamide was notably not found to do this, but this may have simply been due to the fact that the brain penetration of bicalutamide is limited in this species. In any case, enzalutamide is the only approved NSAA that has been found to be associated with a significantly increased incidence of seizures clinically, so the relevance of aforementioned findings with regard to bicalutamide and the other drugs is dubious.
Bicalutamide has a very long serum half-life of about 6 days with a single dose, and a half-life of 7–10 days with repeated administration, allowing for once-daily dosing. It does not have any active metabolites. Steady-state concentrations of the drug are reached after 12 weeks at a dosage of 50 mg/day, with an approximate 10-fold progressive accumulation. However, another source has reported that steady-state levels are reached by one month. Bicalutamide is almost exclusively metabolized by the enzyme CYP3A4. Oral dosages of bicalutamide of 300–600 mg per day result in similar plasma levels of the drug, indicating a saturation of absorption and resulting in similar degrees of efficacy, tolerability, and toxicity.
NSAAs including bicalutamide, flutamide, and nilutamide are non-steroidal anilide (N-phenylamide) derivatives and structural analogues of each other. Bicalutamide is a diarylpropionamide, while flutamide is a monoarylpropionamide and nilutamide is a hydantoin. Bicalutamide and flutamide, though not nilutamide, can also be classified as toluidides. All three of the compounds share a common m-trifluoromethylaniline moiety.
In 1998, researchers discovered the first non-steroidal androgens (the arylpropionamides) via structural modification of bicalutamide. Unlike the purely antiandrogenic bicalutamide, these compounds showed tissue-selective androgenic effects and were classified as selective androgen receptor modulators, or SARMs. Lead SARMs of this series included acetothiolutamide, ostarine (enobosarm; S-1), and andarine (acetamidoxolutamide; S-4).
Bicalutamide was first reported in the literature in June 1987 by Furr et al. The drug was first studied in humans in 1989, and the results of the first phase II clinical trial in prostate cancer were published in 1990. In April and May 1995, AstraZeneca began pre-approval marketing of bicalutamide for the treatment of prostate cancer, and the drug was approved by the U.S. Food and Drug Administration on 4 October 1995. It lost its patent protection in the U.S. in March 2009 and has subsequently been available as a generic, at markedly reduced cost. Bicalutamide was the fourth antiandrogen (and the third NSAA) to be introduced for the treatment of prostate cancer, following the steroidal antiandrogen CPA in 1973 and the NSAAs flutamide and nilutamide in 1975 (1989 in the U.S.) and 1989 (1996 in the U.S.), respectively. All of the NSAAs, including bicalutamide, were derived from flutamide, which was originally synthesized as a bacteriostatic agent in 1967 at Schering Plough Corporation and was subsequently, and serendipitously, found to possess antiandrogen activity.
Society and culture
Sales of bicalutamide (as Casodex) in the U.S. were $1.1 billion in 2005, and it has been described as a "billion-dollar-a-year" drug prior to losing its patent protection. In 2014, despite the introduction of abiraterone acetate in 2011 and enzalutamide in 2012, bicalutamide was still the most commonly prescribed drug in the treatment of metastatic, castration-resistant prostate cancer. Moreover, in spite of being off-patent, bicalutamide was said to still generate a few hundred million dollars in sales per year for AstraZeneca.
Between January 2007 and December 2009 (a period of three years), 1,232,143 prescriptions were written for bicalutamide in the United States, or about 400,000 prescriptions per year. During that time, bicalutamide accounted for about 87.2% of the NSAA market, while flutamide accounted for 10.5% of it and nilutamide for 2.3% of it. Approximately 96% of bicalutamide prescriptions were written for diagnosis codes that clearly indicated neoplasm. About 1,200, or 0.1% of bicalutamide prescriptions were dispensed to pediatric patients (age 0–16).
Bicalutamide has been tested with good results for the treatment of AR-positive ER/PR-negative locally advanced and metastatic breast cancer in a phase II study for this indication. The newer NSAA enzalutamide may also hold some promise for this type of cancer.
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- Lemke TL, Williams DA (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. p. 1288,1290. ISBN 978-0-7817-6879-5.
Nonsteroidal antiandrogens (Fig. 45.16), such as flutamide, nilutamide, and bicalutamide, are referred to as pure antiandrogens, because they bind exclusively to AR and, thus, are devoid of antigonadotropic, antiestrogenic, and progestational effects (112). These agents have advantages over steroidal antiandrogens, such as megestrol acetate or cyproterone acetate (Fig. 45.17), in terms of specificity, selectivity, and pharmacokinetic properties.
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- Schellhammer PF (September 2002). "An evaluation of bicalutamide in the treatment of prostate cancer". Expert Opinion on Pharmacotherapy 3 (9): 1313–28. doi:10.1517/146565184.108.40.2063. PMID 12186624.
- Fradet Y (February 2004). "Bicalutamide (Casodex) in the treatment of prostate cancer". Expert Review of Anticancer Therapy 4 (1): 37–48. doi:10.1586/14737220.127.116.11. PMID 14748655.
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Hormonal therapy is prescribed for male-to-female transsexuals to induce breast formation and a more female distribution of fat and to reduce male-pattern hair growth.19 To achieve these goals, the biologic action of androgens must be almost completely neutralized. Administration of estrogens suppresses gonadotropin output and therefore androgen production, but combining this treatment with a progestational agent, a gonadotropin-releasing-hormone (GnRH) analogue,20 or other medications that suppress androgen action (e.g., cyproterone acetate, flutamide, nilutamide, or bicalutamide) appears to be more effective.21
- Bourgeois AL, Auriche P, Palmaro A, Montastruc JL, Bagheri H (February 2016). "Risk of hormonotherapy in transgender people: Literature review and data from the French Database of Pharmacovigilance". Annales d'Endocrinologie 77 (1): 14–21. doi:10.1016/j.ando.2015.12.001. PMID 26830952.
Drugs for cross-gender hormonal replacement therapy used in the male to female (MtoF) transsexual population. [...] Non-steroidal anti-androgens Bicalutamide, flutamide, nilutamide
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- Klotz L (May 2006). "Combined androgen blockade: an update". The Urologic Clinics of North America 33 (2): 161–6, v–vi. doi:10.1016/j.ucl.2005.12.001. PMID 16631454.
- Wellington K, Keam SJ (2006). "Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer". Drugs 66 (6): 837–50. doi:10.2165/00003495-200666060-00007. PMID 16706554.
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Steroidal androgen receptor blockers (such as Cyproterone) have poorer results for treatment of prostate cancer. [...] Cyproterone acetate (CyA): this steroidal anti-androgen continues to be widely used in many countries, but is gradually being replaced by modern non-steroidal anti-androgens. It not only blocks androgen receptors, but has a mild progesterone-like effect leading to partial inhibition of release of LH by the pituitary gland, with consequent decrease in testosterone level13.
- Payen O, Top S, Vessières A, Brulé E, Lauzier A, Plamont M, McGlinchey MJ, Müller-Bunz H, Jaouen G (2011). "Synthesis and biological activity of ferrocenyl derivatives of the non-steroidal antiandrogens flutamide and bicalutamide" (PDF). Journal of Organometallic Chemistry 696 (5): 1049–1056. doi:10.1016/j.jorganchem.2010.10.051. ISSN 0022-328X.
Cyproterone acetate was one of the first steroidal antiandrogen clinically used but its side-effects, especially the interaction with the progestin and glucocorticoid receptor, made this drug less popular than the nonsteroidal antiandrogens such as nilutamide [3,4], flutamide [5-7] and bicalutamide .
- Chabner BA, Longo DL (8 November 2010). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. p. 679–680. ISBN 978-1-60547-431-1.
From a structural standpoint, antiandrogens are classified as steroidal, including cyproterone [acetate] (Androcur) and megestrol [acetate], or nonsteroidal, including flutamide (Eulexin, others), bicalutamide (Casodex), and nilutamide (Nilandron). The steroidal antiandrogens are rarely used.
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- Vogelzang NJ (September 2012). "Enzalutamide--a major advance in the treatment of metastatic prostate cancer". The New England Journal of Medicine 367 (13): 1256–7. doi:10.1056/NEJMe1209041. PMID 23013078.
The first nonsteroidal antiandrogen agents — flutamide, nilutamide, and bicalutamide2 — were shown to be less effective than castration in cases of metastatic castration-resistant prostate cancer, but bicalutamide is still widely used as a moderately effective secondary hormone therapy because of an excellent safety profile.
- Weber GF (22 July 2015). Molecular Therapies of Cancer. Springer. pp. 318–. ISBN 978-3-319-13278-5.
Compared to flutamide and nilutamide, bicalutamide has a 2-fold increased affinity for the Androgen Receptor, a longer half-life, and substantially reduced toxicities. Based on a more favorable safety profile relative to flutamide, bicalutamide is indicated for use in combination therapy with a Gonadotropin Releasing Hormone analog for the treatment of advanced metastatic prostate carcinoma.
- Kolvenbag GJ, Blackledge GR (1996). "Worldwide activity and safety of bicalutamide: a summary review". Urology 47 (1A Suppl): 70–9; discussion 80–4. PMID 8560681.
Bicalutamide is a new antiandrogen that offers the convenience of once-daily administration, demonstrated activity in prostate cancer, and an excellent safety profile. Because it is effective and offers better tolerability than flutamide, bicalutamide represents a valid first choice for antiandrogen therapy in combination with castration for the treatment of patients with advanced prostate cancer.
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- Moser L (1 January 2008). Controversies in the Treatment of Prostate Cancer. Karger Medical and Scientific Publishers. pp. 41–42. ISBN 978-3-8055-8524-8.
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- Horwich A (11 February 2010). Systemic Treatment of Prostate Cancer. OUP Oxford. pp. 44–. ISBN 978-0-19-956142-1.
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- Klotz L, Schellhammer P (March 2005). "Combined androgen blockade: the case for bicalutamide". Clinical Prostate Cancer 3 (4): 215–9. doi:10.3816/cgc.2005.n.002. PMID 15882477.
- Schellhammer PF, Sharifi R, Block NL, Soloway MS, Venner PM, Patterson AL, Sarosdy MF, Vogelzang NJ, Schellenger JJ, Kolvenbag GJ (September 1997). "Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma: final report of a double-blind, randomized, multicenter trial. Casodex Combination Study Group". Urology 50 (3): 330–6. doi:10.1016/S0090-4295(97)00279-3. PMID 9301693.
- Tombal B, Borre M, Rathenborg P, Werbrouck P, Van Poppel H, Heidenreich A, Iversen P, Braeckman J, Heracek J, Baskin-Bey E, Ouatas T, Perabo F, Phung D, Baron B, Hirmand M, Smith MR (November 2015). "Long-term Efficacy and Safety of Enzalutamide Monotherapy in Hormone-naïve Prostate Cancer: 1- and 2-Year Open-label Follow-up Results". European Urology 68 (5): 787–94. doi:10.1016/j.eururo.2015.01.027. PMID 25687533.
- Balk SP (September 2002). "Androgen receptor as a target in androgen-independent prostate cancer". Urology 60 (3 Suppl 1): 132–8; discussion 138–9. doi:10.1016/S0090-4295(02)01593-5. PMID 12231070.
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- Bigby M, Herxheimer A, Naldi L, et al. (5 June 2014). Evidence-Based Dermatology. Wiley. pp. 1904–. ISBN 978-1-118-35762-0.
- Shapiro J (12 November 2012). Hair Disorders: Current Concepts in Pathophysiology, Diagnosis and Management, An Issue of Dermatologic Clinics. Elsevier Health Sciences. pp. 187–. ISBN 1-4557-7169-4.
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Antiandrogen drugs prevent cellular effects of androgens by blocking intracellular androgen receptors. In this group, spironolactone, cyproteron acetate, finasteride, flutamide, bicalutamide and drospirenone are most frequently used drugs . Since all these drugs are teratogenic, contraception should absolutely be recommended to patients. Treatment period is long and at least a 6-9 months wait is necessary to evaluate the effectiveness of treatment. [...] Bicalutamide is a new, powerful and nonsteroidal pure antiandrogen drug. Its half-life is 7-10 days. It was developed in prostate cancer treatment at a 50 mg/day dose . Low dose bicalutamide (25 mg/day) was shown to be effective in the treatment of hirsutism related to IH and PCOS . It does not have any significant side effects [or] lead to irregular periods.
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Several trials demonstrated complete clearing of acne with flutamide [62,77]. Flutamide used in combination with an [oral contraceptive], at a dose of 500mg/d, flutamide caused a dramatic decrease (80%) in total acne, seborrhea and hair loss score after only 3 months of therapy . When used as a monotherapy in lean and obese PCOS, it significantly improves the signs of hyperandrogenism, hirsutism and particularly acne . [...] flutamide 500mg/d combined with an [oral contraceptive] caused an increase in cosmetically acceptable hair density, in sex of seven women suffering from diffuse androgenetic alopecia .
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Anti-androgens such as flutamide, bicalutamide and cyproterone acetate are also used in patients with prostate cancer and sometimes in male-to-female transgender individuals [...]
- Wierckx K, Gooren L, T'Sjoen G (May 2014). "Clinical review: Breast development in trans women receiving cross-sex hormones". The Journal of Sexual Medicine 11 (5): 1240–7. doi:10.1111/jsm.12487. PMID 24618412.
Other agents with anti-androgenic properties used [in the treatment of transgender women] are nonsteroidal androgen receptor blockers, such as flutamide and bicalutamide [...]
- Deutsch M (17 June 2016), Guidelines for the Primary and Gender-Affirming Care of Transgender and Gender Nonbinary People (PDF) (2nd ed.), University of California, San Francisco: Center of Excellence for Transgender Health, p. 28,
In many countries, cyproterone acetate, a synthetic progestagen with strong anti-androgen activity is commonly used. Cyproterone has been associated with uncommon episodes of fulminant hepatitis. Bicalutamide, a direct anti-androgen used for the treatment of prostate cancer, also has a small but not fully quantified risk of liver function abnormalities (including several cases of fulminant hepatitis); while such risks are acceptable when considering the benefits of bicalutamide in the management of prostate cancer, such risks are less justified in the context of gender affirming treatment. No evidence at present exists to inform such an analysis.
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At 2-year follow-up, loss of spontaneous erections and sexual function occurred in 80 vs. 92% and 78 vs. 88% in the flutamide versus CPA groups, respectively. This group of agents includes flutamide, nilutamide and bicalutamide.
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Nonsteroidal antiandrogens, such as flutamide (50–75 mg/day) and nilutamide (150 mg/day), are also used, but they increase gonadotropin output with a rise of testosterone and estradiol; the rise of estradiol is a desirable effect in this context.
- Jameson JL, de Kretser DM, Marshall JC, De Groot LJ (7 May 2013). Endocrinology Adult and Pediatric: Reproductive Endocrinology. Elsevier Health Sciences. ISBN 978-0-323-22152-8.
Nonsteroidal antiandrogens (e.g., flutamide and nilutamide) are also used, but they increase gonadotropin secretion, causing increased secretion of testosterone and estradiol.119 The latter is desirable in this context, as it has feminizing effects.
- Kreher NC, Pescovitz OH, Delameter P, Tiulpakov A, Hochberg Z (September 2006). "Treatment of familial male-limited precocious puberty with bicalutamide and anastrozole". The Journal of Pediatrics 149 (3): 416–20. doi:10.1016/j.jpeds.2006.04.027. PMID 16939760.
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Therapy with GnRH analogs is expensive and requires intramuscular injections of depot formulations, the insert of a subcutaneous implant yearly, or, much less commonly, daily subcutaneous injections.
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Treatment is expensive, with costs typicall in the range of $10,000–$15,000 per year.
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Antiandrogens are used [...] in conditions such as premature Leydig cell and germ cell maturation in boys to decrease androgen effects if the source of androgens cannot be removed.
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- Boccardo F, Rubagotti A, Battaglia M, Di Tonno P, Selvaggi FP, Conti G, Comeri G, Bertaccini A, Martorana G, Galassi P, Zattoni F, Macchiarella A, Siragusa A, Muscas G, Durand F, Potenzoni D, Manganelli A, Ferraris V, Montefiore F (February 2005). "Evaluation of tamoxifen and anastrozole in the prevention of gynecomastia and breast pain induced by bicalutamide monotherapy of prostate cancer". Journal of Clinical Oncology 23 (4): 808–15. doi:10.1200/JCO.2005.12.013. PMID 15681525.
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A case of near-fatal fulminant hepatic failure in a patient on bicalutamide therapy (50 mg) has recently been published (101), but it is uncertain whether this can be attributed to bicalutamide, as the symptoms developed after only two doses in a patient previously exposed to both cyproterone acetate and flutamide (101).
- Kaplowitz N (16 October 2002). Drug-Induced Liver Disease. CRC Press. pp. 618–. ISBN 978-0-203-90912-6.
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[...] the most commonly prescribed treatment for metastatic castration resistant prostate cancer: bicalutamide. That was sold as AstraZeneca's billion-dollar-a-year drug Casodex before losing patent protection in 2008. AstraZeneca still generates a few hundred million dollars in sales from Casodex, [...]
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