|Trade names||Casodex, Cosudex, Calutide, Calumid, Kalumid, others|
|Drug class||Nonsteroidal antiandrogen|
|Bioavailability||Well-absorbed; absolute bioavailability unknown|
|Protein binding||Racemate: 96.1%
(Mainly to albumin)
• Hydroxylation (CYP3A4)
• Glucuronidation (UGT1A9)
|Metabolites||• Bicalutamide glucuronide
• Hydroxybicalutamide gluc.
|Biological half-life||Acute: 5.8 days
Chronic: 7–10 days
|Chemical and physical data|
|Molar mass||430.373 g/mol|
|3D model (JSmol)|
|Chirality||Racemic mixture (of (R)- and (S)-enantiomers)|
|Melting point||191 to 193 °C (376 to 379 °F) (experimental)|
|Boiling point||650 °C (1,202 °F) (predicted)|
|Solubility in water||0.005 mg/mL (20 °C)|
|(what is this?)|
Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer. It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer. Bicalutamide may also be used to treat excessive hair growth in women, as a component of hormone therapy for transgender women, to treat early puberty in boys, and to prevent priapism. It is taken by mouth.
Common side effects in men include breast enlargement, breast tenderness, and hot flashes. Other side effects in men include feminization and sexual dysfunction. While the medication appears to produce few side effects in women, its use in women is not recommended by the Food and Drug Administration (FDA). Use during pregnancy may harm the baby. Bicalutamide causes elevated liver enzymes in around 1% of people. Rarely, it has been associated with cases of liver damage, lung toxicity, and sensitivity to light. Although the risk of adverse liver changes is small, monitoring of liver enzymes is recommended during treatment.
Bicalutamide is a member of the nonsteroidal antiandrogen (NSAA) group of medications, it works by blocking the androgen receptor (AR), the biological target of the androgen sex hormones testosterone and dihydrotestosterone (DHT). It does not lower androgen levels, the medication can have some estrogen-like effects in men. Bicalutamide is well-absorbed, and its absorption is not affected by food, the elimination half-life of the medication is around one week. It is believed to cross the blood–brain barrier and affect both the body and brain.
Bicalutamide was patented in 1982 and approved for medical use in 1995, it is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Bicalutamide is available as a generic medication, the wholesale cost in the developing world is about US$7.07 to US$144.22 per month. In the United States it costs about US$10 and above per month, the drug is sold in more than 80 countries, including most developed countries. It is the most widely used antiandrogen in the treatment of prostate cancer, and has been prescribed to millions of men with the disease.
- 1 Medical uses
- 2 Contraindications
- 3 Side effects
- 4 Overdose
- 5 Interactions
- 6 Pharmacology
- 6.1 Pharmacodynamics
- 6.1.1 Antiandrogenic activity
- 6.1.2 Drug levels, androgen levels, and efficacy
- 6.1.3 Influences on hormone levels
- 6.1.4 Differences from castration
- 6.1.5 Paradoxical stimulation of late-stage prostate cancer
- 6.1.6 Induction of breast development
- 6.1.7 Effects on spermatogenesis and fertility
- 6.1.8 Other activities
- 6.2 Pharmacokinetics
- 6.1 Pharmacodynamics
- 7 Chemistry
- 8 History
- 9 Society and culture
- 10 Research
- 11 Veterinary use
- 12 See also
- 13 References
- 14 Further reading
- 15 External links
- Metastatic prostate cancer (mPC) in men in combination with a gonadotropin-releasing hormone (GnRH) analogue or orchiectomy at moderate doses
- Locally advanced prostate cancer (LAPC) in men as a monotherapy in high doses
It can also be and is used to a lesser extent for the following off-label (non-approved) indications:
- Androgen-dependent skin and hair conditions such as acne, seborrhea, hirsutism, and pattern hair loss (androgenic alopecia) in women at low doses, generally in combination with an oral contraceptive
- Hyperandrogenism such as due to polycystic ovary syndrome (PCOS) or congenital adrenal hyperplasia (CAH) in women
- Hormone therapy for transgender women in combination with an estrogen (e.g., estradiol)
- Precocious puberty in boys in moderate doses, especially due to familial male-limited precocious puberty (testotoxicosis)
- Priapism in men at low to very low doses
It has been suggested for but has uncertain effectiveness in the following indications:
- Hypersexuality and paraphilias, particularly in combination with chemical castration
Bicalutamide is available for the treatment of prostate cancer in most developed countries, including over 80 countries worldwide. Bicalutamide is available in 50 mg, 80 mg (in Japan), and 150 mg tablets for oral administration. The drug is registered for use as a 150 mg/day monotherapy for the treatment of LAPC in at least 55 countries, with the U.S. being a notable exception where it is registered only for use at a dosage of 50 mg/day in combination with castration. No other formulations or routes of administration are available or used. All formulations of bicalutamide are specifically indicated for the treatment of prostate cancer alone or in combination with surgical or medication castration. A combined formulation of bicalutamide and the GnRH agonist goserelin in which goserelin is provided as a subcutaneous implant for injection and bicalutamide is included as 50 mg tablets for oral ingestion is marketed in Australia and New Zealand under the brand name ZolaCos CP (Zoladex–Cosudex Combination Pack).
In individuals with severe, though not mild-to-moderate hepatic impairment, there is evidence that the elimination of bicalutamide is slowed, and hence, caution may be warranted in these patients; in severe hepatic impairment, the elimination half-life of the active (R)-enantiomer of bicalutamide is increased by about 1.75-fold (76% increase; elimination half-life of 5.9 and 10.4 days for normal and impaired patients, respectively). The elimination half-life of bicalutamide is unchanged in renal impairment.
Pregnancy and breastfeeding
Bicalutamide is pregnancy category X, or "contraindicated in pregnancy", in the U.S., and pregnancy category D, the second most restricted rating, in Australia. As such, it 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 adequate contraception, it is unknown whether bicalutamide is excreted in breast milk, but many drugs are excreted in breast milk, and for this reason, bicalutamide treatment is similarly not recommended while breastfeeding.
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. In pregnant rats given bicalutamide at a dosage of 10 mg/kg/day (resulting in circulating drug levels approximately equivalent to two-thirds of human therapeutic concentrations) and above, feminization of male offspring, such as reduced anogenital distance and hypospadias, as well as impotence, were observed. No other teratogenic effects were observed in rats or rabbits receiving up to very high dosages of bicalutamide (that corresponded to up to approximately two times human therapeutic levels), and no teratogenic effects of any sort were observed in female rat offspring at any dosage, as such, bicalutamide is a selective reproductive teratogen in males, and may have the potential to produce undervirilization/sexually ambiguous genitalia in male fetuses.
The side effect profile of bicalutamide is highly dependent on sex; that is, on whether the person is male or female. In men, due to androgen deprivation, a variety of side effects of varying severity may occur during bicalutamide treatment, with breast pain/tenderness and gynecomastia (breast development/enlargement) being the most common. In addition breast changes, physical feminization and demasculinization in general, including reduced body hair growth, decreased muscle mass and strength, feminine changes in fat mass and distribution, and reduced penile length, may also occur in men. Other side effects that have been observed in men and that are similarly related to androgen deprivation include hot flashes, sexual dysfunction (e.g., loss of libido, erectile dysfunction), depression, fatigue, weakness, anemia, and decreased semen/ejaculate volume. In women, on the other hand, due to the little biological importance of androgens in this sex, the side effects of pure antiandrogens or NSAAs are minimal, and bicalutamide has been found to be very well-tolerated. General side effects of bicalutamide that may occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash. The drug is well-tolerated at higher dosages than the 50 mg/day dosage, with rare additional side effects.
Bicalutamide monotherapy has been associated with abnormal liver function tests such as elevated liver enzymes in 3.4% of men relative to 1.9% for standard care. Hepatic changes such as marked increases in liver enzymes or hepatitis that necessitated discontinuation of bicalutamide have occurred in approximately 0.3 to 1% of men in clinical trials. Monitoring of liver function during treatment is recommended, particularly in the first few months; in men of advanced age with prostate cancer, bicalutamide monotherapy has been associated with an increase in non-prostate cancer mortality, in part due to an increase in the rate of heart failure. These mortality-related effects are thought to be a consequence of androgen deprivation, rather than a specific drug-related toxicity of bicalutamide.
Five cases of hepatotoxicity or liver failure, two of which resulted in death, have been reported with bicalutamide. Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice. Bicalutamide has also been associated with several case reports of interstitial pneumonitis, which can potentially progress to pulmonary fibrosis. Symptoms that may indicate lung dysfunction include dyspnea (difficult breathing or shortness of breath), cough, and pharyngitis (inflammation of the pharynx, resulting in sore throat). Both hepatotoxicity and interstitial pneumonitis are said to be extremely rare events with bicalutamide. A few cases of photosensitivity have been reported with bicalutamide. Hypersensitivity reactions (drug allergy) like angioedema and hives have also uncommonly been reported in association with bicalutamide.
A single oral dose of bicalutamide in humans that results in symptoms of overdose or that is considered to be life-threatening has not been established. Dosages of up to 600 mg/day have been well-tolerated in clinical trials, and it is notable that there is a saturation of absorption with bicalutamide such that circulating levels of its active (R)-enantiomer do not further increase above a dosage of 300 mg/day. Overdose is considered to be unlikely to be life-threatening with bicalutamide or other first-generation NSAAs (i.e., flutamide and nilutamide). A massive overdose of nilutamide (13 grams, or 43 times the normal maximum 300 mg/day clinical dosage) in a 79-year-old man was uneventful, producing no clinical signs or symptoms or toxicity. There is no specific antidote for bicalutamide or NSAA overdose, and treatment should be based on symptoms.
Cytochrome P450 enzymes
Bicalutamide is almost exclusively metabolized by CYP3A4, as such, its levels in the body may be altered by inhibitors and inducers of CYP3A4. (For a list of CYP3A4 inhibitors and inducers, see here.) However, in spite of the fact bicalutamide is metabolized by CYP3A4, there is no evidence of clinically significant drug interactions when bicalutamide at a dosage of 150 mg/day or less is co-administered with drugs that inhibit or induce cytochrome P450 enzyme activity.
Plasma binding proteins
Because bicalutamide circulates at relatively high concentrations and is highly protein-bound, it has the potential to displace other highly protein-bound drugs like warfarin, phenytoin, theophylline, and aspirin from plasma binding proteins. This could, in turn, result in increased free concentrations of such drugs and increased effects and/or side effects, potentially necessitating dosage adjustments. Bicalutamide has specifically been found to displace coumarin anticoagulants like warfarin from their plasma binding proteins (namely albumin) in vitro, potentially resulting in an increased anticoagulant effect, and for this reason, close monitoring of prothrombin time and dosage adjustment as necessary is recommended when bicalutamide is used in combination with these drugs. However, in spite of this, no conclusive evidence of an interaction between bicalutamide and other drugs was found in clinical trials of nearly 3,000 patients.
Bicalutamide acts as a highly selective competitive silent antagonist of the AR (IC50 = 159–243 nM). It has no capacity to activate the AR under normal physiological circumstances (see below). In addition to competitive antagonism of the AR, bicalutamide has been found to accelerate the degradation of the AR, and this action may also be involved in its activity as an antiandrogen. 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. Levels of the (R)-isomer also notably are 100-fold higher than those of the (S)-isomer at steady-state.
Owing to its selectivity for the AR, unlike SAAs such as CPA and megestrol acetate, bicalutamide does not bind to other steroid hormone receptors, and for this reason, has no additional, off-target hormonal activity (estrogenic or antiestrogenic, progestogenic or antiprogestogenic, glucocorticoid or antiglucocorticoid, or mineralocorticoid or antimineralocorticoid); nor does it inhibit 5α-reductase. However, it significantly increases estrogen levels secondary to blockade of the AR in males, and for this reason, does have some indirect estrogenic effects in men. Also in contrast to SAAs, bicalutamide neither inhibits nor suppresses androgen production in the body (i.e., it does not act as an antigonadotropin or steroidogenesis inhibitor), and instead exclusively mediates its antiandrogen effects by blocking androgen binding and subsequent receptor activation at the level of the AR.
In addition to the classical nuclear AR, bicalutamide has also been identified as a potent antagonist of ZIP9, a membrane androgen receptor (mAR) and zinc transporter protein, with an IC50 of 66.3 nM (relative to Kd = 17.9 nM for testosterone). This protein appears to be involved in prostate cancer and breast cancer. Bicalutamide failed to affect testosterone signaling mediated by GPRC6A, another mAR, on the other hand.
Drug levels, androgen levels, and efficacy
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, sufficiently high relative concentrations of bicalutamide (1,000-fold excess) are effective in preventing activation of the AR by androgens like DHT and testosterone and subsequent upregulation of the transcription of androgen-responsive genes. At steady-state, relative to the normal adult male range for testosterone levels (300–1,000 ng/dL), circulating concentrations of bicalutamide at 50 mg/day are 600 to 2,500 times higher and at 150 mg/day 1,500 to 8,000 times higher than circulating testosterone levels, while bicalutamide concentrations, relative to the mean testosterone levels present in men who have been surgically castrated (15 ng/dL), are 42,000 times higher than testosterone levels at 50 mg/day.
Whereas testosterone is the major circulating androgen, DHT is the major androgen in the prostate gland. DHT levels in circulation are relatively low and only approximately 10% of those of circulating testosterone levels. Conversely, local concentrations of DHT in the prostate gland are 5- to 10-fold higher than circulating levels of DHT. This is due to high expression of 5α-reductase in the prostate gland, which very efficiently catalyzes the formation of DHT from testosterone such that over 90% of intraprostatic testosterone is converted into DHT. Relative to testosterone, DHT is 2.5- to 10-fold as potent as an AR agonist in bioassays, and hence, is a much stronger androgen in comparison. As such, AR signaling is exceptionally high in the prostate gland, and the effectiveness of bicalutamide monotherapy in the treatment of prostate cancer, which is roughly equivalent to that of GnRH analogues, is a reflection of its capacity to strongly and efficaciously antagonize the AR at clinically used dosages. On the other hand, GnRH analogues achieve only a 50 to 60% reduction in levels of DHT in the prostate gland, and the combination of a GnRH analogue and bicalutamide is significantly more effective than either modality alone in the treatment of prostate cancer.
In women, total testosterone levels are 20-fold and free testosterone levels 40-fold lower relative to men; in addition, whereas bicalutamide monotherapy can increase testosterone levels by up to 2-fold in men, the drug does not increase testosterone levels in women (see below). For these reasons, much lower dosages of bicalutamide (e.g., 25 mg/day in the hirsutism studies) may be used in women with comparable antiandrogen effectiveness.
Influences on hormone levels
In men, blockade of the AR by bicalutamide in the pituitary gland and hypothalamus prevents 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 an increase in androgen and estrogen levels. At a dosage of 150 mg/day, bicalutamide has been found to increase testosterone levels by about 1.5- to 2-fold (59–97% increase) and estradiol levels by about 1.5- to 2.5-fold (65–146% increase). Levels of DHT are also increased to a lesser extent (by 25%), and concentrations of sex hormone-binding globulin (SHBG) and prolactin increase as well (by 8% and 40%, respectively) secondary to the increase in estradiol levels. The estradiol concentrations produced in men by bicalutamide monotherapy are said to approximate the low-normal estradiol levels of a premenopausal woman, while testosterone levels generally remain in the high end of the normal male range and rarely exceed it. 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 (notably providing indication that the drug has clinically-relevant antiandrogen effects in males at a dosage as low as 10 mg/day). It is important to note that bicalutamide increases androgen and estrogen levels only in men and not in women; this is because androgen levels are comparatively far lower in women and in turn exert little to no basal suppression of the hypothalamic–pituitary–gonadal (HPG) axis.
The reason that testosterone levels are elevated but almost always remain in the normal male range with bicalutamide monotherapy is thought to be due to the concomitantly increased levels of estradiol, as estradiol is potently antigonadotropic and limits secretion of LH. In fact, estradiol is a much stronger inhibitor of gonadotropin secretion than is testosterone, and even though circulating concentrations of estradiol are far lower than those of testosterone in men, it is said that estradiol is nonetheless likely the major feedback regulator of gonadotropin secretion in this sex; in accordance, clomifene, a SERM with antiestrogenic activity, has been found to increase testosterone levels to as much as 250% of initial values in men with hypogonadism, and a study of clomifene treatment in normal men observed increases in FSH and LH levels of 70–360% and 200–700%, respectively, with increases in testosterone levels that were similar to the increases seen with the gonadotropins. In addition to systemic or circulating estradiol, local aromatization of testosterone into estradiol in the hypothalamus and pituitary gland may contribute to suppression of gonadotropin secretion.
Bicalutamide more than blocks the effects of the increased testosterone levels that it induces in men, which is evidenced by the fact that monotherapy with the drug is about as effective as GnRH analogue therapy in the treatment of prostate cancer. However, in contrast, the effects of the elevated estrogen levels remain unopposed by bicalutamide, and this is largely responsible for the feminizing side effects (e.g., gynecomastia) of the drug in men.
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, CAB, 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 additionally a potent GABAA receptor-potentiating neurosteroid. Due to the fact that bicalutamide does not lower testosterone levels, the levels of these metabolites would not be expected to be lowered either, unlike with therapies such as GnRH analogues. (Indeed, testosterone, DHT, and estradiol levels are actually raised by bicalutamide treatment, and for this reason, levels of 3α- and 3β-androstanediol might be elevated to some degree similarly.) These metabolites of testosterone 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.
Paradoxical stimulation of late-stage 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 (LBD) 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.
Induction of breast development
In transgender women, breast development is a desired effect of antiandrogen and/or estrogen treatment. Bicalutamide induces breast development (or gynecomastia) in biologically male individuals by two mechanisms: 1) blocking androgen signaling in breast tissue; and 2) increasing estrogen levels. Estrogen is responsible for the induction of breast development under normal circumstances, while androgens powerfully suppress estrogen-induced breast growth, it has been found that very low levels of estrogen can induce breast development in the presence of low or no androgen signaling. In accordance, bicalutamide not only induces gynecomastia at a high rate when given to men as a monotherapy, it results in a higher incidence of gynecomastia in combination with a GnRH analogue relative to GnRH analogue treatment alone (in spite of the presence of only castrate levels of estrogen in both cases).
A study of men treated with NSAA (flutamide or bicalutamide) monotherapy for prostate cancer found that NSAAs induced full ductal development and moderate lobuloalveolar development of the breasts from a histological standpoint. The study also found that, in contrast, treatment of transgender women with estrogen and CPA (which is progestogenic in addition to antiandrogenic, unlike NSAAs) resulted in full lobuloalevolar development, as well as pregnancy-like breast hyperplasia in two of the subjects. In addition, it was observed that the lobuloalveolar maturation reversed upon discontinuation of CPA after sex reassignment surgery (that is, surgical castration) in these individuals. It was concluded that progestogen in addition to antiandrogen/estrogen treatment is required for the induction of full female-like histological breast development (i.e., that includes complete lobuloalveolar maturation), and that continued progestogen treatment is necessary to maintain such maturation. It should be noted however that although these findings may have important implications in the contexts of lactation and breastfeeding, epithelial tissue accounts for approximately only 10% of breast volume (with the bulk of the breasts (80–90%) being represented by stromal or adipose tissue), and it is uncertain to what extent, if any, that development of lobuloalveolar structures (a form of epithelial tissue) contributes to breast size and/or shape.
Effects on spermatogenesis and fertility
Spermatogenesis and male fertility are dependent on FSH, LH, and high levels of testosterone within the testicles. LH does not seem to be involved in spermatogenesis outside of its role in inducing production of testosterone by the Leydig cells in the seminiferous tubules (which make up approximately 80% of the bulk of the testes), whereas this is not the case for FSH, which is importantly involved. In accordance with the fact that the testes are the source of 95% of circulating testosterone in the body, local levels of testosterone inside of the testes are extremely high, ranging from 20- to 200-fold higher than circulating concentrations. Moreover, high levels of testosterone within the testes are required for spermatogenesis, although only a small fraction (5–10%) of normal levels appears to actually be necessary for spermatogenesis.
Unlike with antigonadotropic antiandrogens like 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 extremely high local levels of testosterone in the testes, in that it is likely that systemic bicalutamide therapy is unable to achieve concentrations of the drug within the testes that are able to considerably block androgen signaling in this part of the body, this is particularly so considering that bicalutamide increases circulating testosterone levels, and by extension gonadal testosterone production, by up to two-fold in males, and that only a small fraction of normal intratesticular testosterone levels, and by extension androgen action, appears to be necessary to maintain spermatogenesis.
In contrast to bicalutamide and other pure antiandrogens or NSAAs, antigonadotropic antiandrogens suppress gonadotropin secretion, which in turn diminishes testosterone production by the testes as well as the maintenance of the testes by FSH, 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.
Treatment of men with exogenous testosterone or other AAS results in suppression of gonadotropin secretion and gonadal testosterone production due to their antigonadotropic effects or activation of the AR in the pituitary gland, resulting in inhibition or abolition of spermatogenesis and fertility:
Treatment of an infertile man with testosterone does [not] improve spermatogenesis, since exogenous administrated testosterone and its metabolite estrogen will suppress both GnRH production by the hypothalamus and luteinizing hormone production by the pituitary gland and subsequently suppress testicular testosterone production. Also, high levels of testosterone are needed inside the testis and this can never be accomplished by oral or parenteral administration of androgens. Suppression of testosterone production by the leydig cells will result in a deficient spermatogenesis, as can be seen in men taking anabolic–androgenic steroids.
In contrast, pure AR antagonists would, in theory, result in the opposite (although reduced semen volume and sexual dysfunction may occur):
It is theoretically a sound hypothesis that the spermatogenesis can be increased by indirectly stimulating FSH and LH secretions from the pituitary gland. However, for this to fructify, it requires the use of testosterone antagonist to nullify the negative feedback effect of circulating testosterone on the release of FSH and LH, thus augmenting the secretion of testosterone and spermatogenesis. Unfortunately, a testosterone antagonist will be unacceptable to males, as it may reduce secondary sexual functions including erection and ejaculation that is vital for the successful fertilization.
Although bicalutamide alone would appear to have minimal detrimental effect on spermatogenesis and male fertility, other hormonal agents that bicalutamide may be combined with, including GnRH analogues and particularly estrogens (as in transgender hormone therapy), can have a considerable detrimental effect on fertility. This is largely a consequence of their antigonadotropic activity. Antigonadotropic agents like high-dose CPA, high-dose androgens (e.g., testosterone esters), and GnRH antagonists (though notably not GnRH agonists) produce hypogonadism and high rates of severe or complete infertility (e.g., severe oligospermia or complete azoospermia) in men. However, these effects are fully and often rapidly reversible with their discontinuation, even after prolonged treatment; in contrast, while estrogens at sufficiently high dosages similarly are able to produce hypogonadism and to abolish or severely impair spermatogenesis, this is not necessarily reversible in the case of estrogens and can be long-lasting after prolonged exposure. The difference is attributed to an apparently unique, direct adverse effect of high concentrations of estrogens on the Leydig cells of the testes.
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 (cholesterol 27-hydroxylase) 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 (ER) (it has been characterized as a selective estrogen receptor modulator) 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. In addition to CYP27A1, bicalutamide has been found to bind to and inhibit CYP46A1 (cholesterol 24-hydroxylase) in vitro, but this has yet to be assessed and confirmed in vivo.
Bicalutamide, as well as enzalutamide, have been found to act as inhibitors of P-glycoprotein efflux and ATPase activity. This action may reverse docetaxel resistance in prostate cancer cells by reducing transport of the drug out of these cells.
All of the NSAAs approved for the treatment of prostate cancer have been found to possess an off-target action of acting as weak non-competitive inhibitors of human GABAA receptor currents in vitro to varying extents. The IC50 values are 44 μM for flutamide (as hydroxyflutamide), 21 μM for nilutamide, 5.2 μM for bicalutamide, and 3.6 μM for enzalutamide. In addition, flutamide, nilutamide, and enzalutamide have been found to cause convulsions and/or death in mice at sufficiently high doses. Bicalutamide was notably not found to do this, but this was likely simply due to the limited central nervous system penetration of bicalutamide 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 and other associated side effects clinically, so the relevance of the aforementioned findings with regard to bicalutamide and the other NSAAs is unclear.
The pharmacokinetics of bicalutamide are unaffected by food, age, body weight, renal impairment, and mild-to-moderate hepatic impairment. However, it has been observed that steady-state concentrations of bicalutamide are higher in Japanese individuals than in Caucasians, indicating that ethnicity may be associated with differences in the pharmacokinetics of bicalutamide in some instances.
Bicalutamide is extensively and well-absorbed following oral administration, and its absorption is not affected by food, the absolute bioavailability of bicalutamide in humans is unknown due to its very low water solubility and hence lack of an assessable intravenous formulation. However, the absolute bioavailability of bicalutamide has been found to be high in animals at low doses (72% in rats at 1 mg/kg; 100% in dogs at 0.1 mg/kg), but diminishes with increasing doses such that the bioavailability of bicalutamide is low at high doses (10% in rats at 250 mg/kg; 31% in dogs at 100 mg/kg). In accordance, absorption of (R)-bicalutamide in humans is slow and extensive but saturable, with steady-state levels increasing linearly at a dosage of up to 50 mg/day and non-linearly at higher dosages.
At higher dosages of 100 to 200 mg/day, absorption of bicalutamide is approximately linear, with a small but increasing departure from linearity above 150 mg/day. In terms of geometric mean steady-state concentrations of (R)-bicalutamide, the departures from linearity were 4%, 13%, 17%, and 32% with dosages of 100, 150, 200, and 300 mg/day, respectively. There is a plateau in steady-state levels of (R)-bicalutamide with bicalutamide dosages above 300 mg/day, and, accordingly, dosages of bicalutamide of 300 to 600 mg/day result in similar circulating concentrations of (R)-bicalutamide and similar degrees clinically of efficacy, tolerability, and toxicity. Relative to 150 mg/day bicalutamide, levels of (R)-bicalutamide are about 15% higher at a dosage of 200 mg/day and about 50% higher at a dosage of 300 mg/day. In contrast to (R)-bicalutamide, the inactive enantiomer (S)-bicalutamide is much more rapidly absorbed (as well as cleared from circulation).
|50 mg||150 mg|
|tmax||31 hours||39 hours|
|tss||4–12 weeks||4–12 weeks|
Steady-state concentrations of the drug are reached after 4 to 12 weeks of administration independently of dosage, with an approximate 10- to 20-fold progressive accumulation of circulating levels of (R)-bicalutamide. In spite of the relatively long time to reach steady-state (which is a product of its long elimination half-life), there is evidence that the achieved AR blockade of bicalutamide is equivalent to that of flutamide by the end of the first day of treatment. With single 50 mg and 150 mg doses of bicalutamide, mean peak concentrations (Cmax) of (R)-bicalutamide are 0.77 μg/mL (1.8 μmol/L) (at 31 hours) and 1.4 μg/mL (3.3 μmol/L) (at 39 hours), respectively. At steady-state, mean circulating concentrations (Css) of (R)-bicalutamide with 50 mg/day and 150 mg/day bicalutamide are 8.9 μg/mL (21 μmol/L) and 22 μg/mL (51 μmol/L), respectively. In another 150 mg/day bicalutamide study, mean circulating concentrations of (R)-bicalutamide were 19.4 μg/mL (45.1 μmol/L) and 28.5 μg/mL (66.3 μmol/L) on days 28 and 84 (weeks 4 and 12) of treatment, respectively.
The tissue distribution of bicalutamide is not well-characterized. However, it has been reported that distribution studies with bicalutamide have shown that preferential (i.e., tissue-selective) accumulation in anabolic (e.g., muscle) tissues does not occur. There are no available data on hepatic bicalutamide concentrations in humans, but a rat study found that oral bicalutamide treatment resulted in 4-fold higher concentrations of the drug in the liver relative to plasma (a common finding with orally administered drugs, due to transfer through the hepatic portal system prior to reaching circulation). In men receiving 150 mg/day bicalutamide, concentrations of (R)-bicalutamide in semen were 4.9 μg/mL (11 μmol/L), and the amount of the drug that could potentially be delivered to a female partner during sexual intercourse is regarded as low (estimated at 0.3 μg/kg) and below the amount that is required to induce changes in the offspring of laboratory animals. Bicalutamide is highly protein-bound (96.1% for racemic bicalutamide, 99.6% for (R)-bicalutamide), mainly to albumin. It has negligible affinity for SHBG and no affinity for corticosteroid-binding globulin.
Based on animal research, it was initially thought that bicalutamide was unable to cross the blood–brain barrier into the central nervous system and hence would be a peripherally-selective antiandrogen in humans. This conclusion was drawn from the finding that bicalutamide does not increase LH or testosterone levels in multiple tested animal species (including rats and dogs), as antiandrogens like flutamide normally do this by blocking ARs in the pituitary gland and hypothalamus in the brain and thereby disinhibiting the HPG axis. In humans however, bicalutamide has been found to increase LH and testosterone levels, and to a comparable extent relative to flutamide and nilutamide. As such, it appears that there are species differences in the central penetration of bicalutamide and that the drug does indeed cross the blood–brain barrier and affect central function in humans, as supported by potential side effects, in spite of increased testosterone levels, like hot flashes and diminished sexual interest in men. A newer NSAA, darolutamide, has been found to negligibly cross the blood–brain barrier in both animals and humans, and in accordance, unlike bicalutamide, does not increase LH or testosterone levels in humans.
The metabolism of bicalutamide is hepatic and stereoselective, the inactive (S)-enantiomer is metabolized mainly by glucuronidation and is rapidly cleared from circulation, while the active (R)-isomer is slowly hydroxylated and then glucuronidated. In accordance, the active (R)-enantiomer has a far longer elimination half-life than the (S)-isomer, and circulating levels of (R)-bicalutamide are 10- to 20-fold and 100-fold higher than those of (S)-bicalutamide after a single dose and at steady-state, respectively. (R)-Bicalutamide is almost exclusively metabolized via hydroxylation into (R)-hydroxybicalutamide by the cytochrome P450 enzyme CYP3A4. Bicalutamide is also glucuronidated by UGT1A9, a UDP-glucuronyltransferase, into bicalutamide glucuronide, and (R)-hydroxybicalutamide glucuronide is formed from the metabolism of (R)-hydroxybicalutamide by UGT1A9. Similar to the inactive (S)-enantiomer of bicalutamide, (R)-hydroxybicalutamide is glucuronidated and rapidly cleared from circulation. None of the metabolites of bicalutamide are known to be active. Following administration of bicalutamide, only low concentrations of the metabolites are detectable in blood plasma, while unchanged bicalutamide predominates. (R)-Bicalutamide has a long elimination half-life of 5.8 days with a single dose, and an elimination half-life of 7–10 days with repeated administration, which allows for convenient once-daily dosing of bicalutamide.
Bicalutamide is eliminated in feces (43%) and urine (34%), whereas its metabolites are eliminated in approximately equal proportions in urine and bile. It is excreted to a substantial extent in its unmetabolized form, with both bicalutamide and its metabolites excreted mainly as glucuronide conjugates.
Bicalutamide is a racemic mixture consisting of equal proportions of enantiomers (R)-bicalutamide (dextrorotatory) and (S)-bicalutamide (levorotatory). Its systematic name (IUPAC) is (RS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide. The compound has a chemical formula of C18H14F4N2O4S, a molecular weight of 430.373 g/mol, and is a fine white to off-white powder.
The acid dissociation constant (pKa') of bicalutamide is approximately 12, it is a highly lipophilic compound (log P = 2.92). At 37 °C (98.6 °F), or normal human body temperature, bicalutamide is practically insoluble in water (4.6 mg/L), acid (4.6 mg/L at pH 1), and alkali (3.7 mg/L at pH 8). In organic solvents, it is slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and freely soluble in acetone and tetrahydrofuran.
Bicalutamide is a synthetic and nonsteroidal compound which was derived from flutamide. It can be classified as and has variously been referred to as an anilide (N-phenylamide; or aniline), a diarylpropionamide, and a toluidide.
First-generation NSAAs including bicalutamide, flutamide, and nilutamide are all synthetic, nonsteroidal anilide 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 3-trifluoromethylaniline moiety. Bicalutamide is a modification of flutamide in which a 4-fluorophenylsulfonyl moiety has been added and the nitro group on the original phenyl ring has been replaced with a cyano group. Topilutamide, also known as fluridil, is another NSAA that is closely related structurally to the first-generation NSAAs, but, in contrast to them, is not used in the treatment of prostate cancer and is instead used exclusively as a topical antiandrogen in the treatment of androgenic alopecia.
The second-generation NSAAs enzalutamide and apalutamide were derived from and are analogues of the first-generation NSAAs, while another second-generation NSAA, darolutamide, is said to be structurally distinct and chemically unrelated to the other NSAAs. Enzalutamide is a modification of bicalutamide in which the inter-ring linking chain has been altered and cyclized into a 5,5-dimethyl-4-oxo-2-thioxo imidazolidine moiety. In apalutamide, the 5,5-dimethyl groups of the imidazolidine ring of enzalutamide are cyclized to form an accessory cyclobutane ring and one of its phenyl rings is replaced with a pyridine ring.
The first nonsteroidal androgens (the arylpropionamides) were discovered via structural modification of bicalutamide. Unlike bicalutamide (which is purely antiandrogenic), these compounds show tissue-selective androgenic effects and were classified as selective androgen receptor modulators (SARMs). Lead SARMs of this series included acetothiolutamide, enobosarm (ostarine; S-22), and andarine (acetamidoxolutamide or androxolutamide; S-4). They are very close to bicalutamide structurally, with the key differences being that the linker sulfone of bicalutamide has been replaced with an ether or thioether group to confer agonism of the AR and the 4-fluoro atom of the pertinent phenyl ring has been substituted with an acetamido or cyano group to eliminate reactivity at the position.
Radiotracers for medical imaging
A few radiolabeled derivatives of bicalutamide have been developed for potential use as radiotracers in medical imaging, they include [18F]bicalutamide, 4-[76Br]bromobicalutamide, and [76Br]bromo-thiobicalutamide, the latter two were found to have substantially increased affinity for the AR relative to that of bicautamide. However, none of these agents have been evaluated in humans.
5N-Bicalutamide, or 5-azabicalutamide, is a minor structural modification of bicalutamide which acts as a reversible covalent antagonist of the AR and has approximately 150-fold higher affinity for the AR and about 20-fold greater functional inhibition of the AR relative to bicalutamide. It is among the most potent AR antagonists ever to have been developed and is being researched for potential use in the treatment of antiandrogen-resistant prostate cancer.
A number of chemical syntheses of bicalutamide have been published in the literature. The procedure of the first published chemical synthesis of bicalutamide (Tucker et al., 1988) can be seen below.
Bicalutamide as well as all of the other currently marketed NSAAs were derived from structural modification of flutamide, which itself was originally synthesized as a bacteriostatic agent in 1967 at Schering Plough Corporation and was subsequently and serendipitously found to possess antiandrogenic activity. Bicalutamide was discovered by Tucker and colleagues at Imperial Chemical Industries in the 1980s and was selected for development from a group of over 1,000 synthesized compounds. It was first patented in 1982 and was first reported in the scientific literature in June 1987.
Bicalutamide was first studied in a phase I clinical trial in 1987 and the results of the first phase II clinical trial in prostate cancer were published in 1990. The pharmaceutical division of ICI was split out into an independent company called Zeneca in 1993, and in April and May 1995, Zeneca (now AstraZeneca, after merging with Astra AB in 1999) began pre-approval marketing of bicalutamide for the treatment of prostate cancer in the U.S.. It was first launched in the U.K. in May 1995, and was subsequently approved by the U.S. FDA on 4 October 1995, for the treatment of prostate cancer at a dosage of 50 mg/day in combination with a GnRH analogue.
Following its introduction for use in combination with a GnRH analogue, bicalutamide was developed as a monotherapy at a dosage of 150 mg/day for the treatment of prostate cancer, and was approved for this indication in Europe, Canada, and a number of other countries in the early 2000s. This application of bicalutamide was also under review by the FDA in the U.S. in 2002, but ultimately was not approved in this country. In Japan, bicalutamide is licensed at a dosage of 80 mg/day alone or in combination with a GnRH analogue for prostate cancer. The unique 80 mg dosage of bicalutamide used in Japan was selected for development in this country on the basis of observed pharmacokinetic differences with bicalutamide in Japanese men.
Subsequent to negative findings of bicalutamide monotherapy for LPC in the EPC trial, approval of bicalutamide for use specifically in the treatment of LPC was withdrawn in a number of countries including the U.K. (in October or November 2003) and several other European countries and Canada (in August 2003). In addition, the U.S. and Canada explicitly recommended against the use of 150 mg/day bicalutamide for this indication. The drug is effective for, remains approved for, and continues to be used in the treatment of LAPC and mPC, on the other hand.
Bicalutamide was the fourth antiandrogen (and the third NSAA) to be introduced for the treatment of prostate cancer, following the SAA CPA in 1973 and the NSAAs flutamide in 1983 (1989 in the U.S.) and nilutamide in 1989 (1996 in the U.S.). It has been followed by abiraterone acetate in 2011 and enzalutamide in 2012, and may also be followed by in-development drugs such as apalutamide, darolutamide, and seviteronel.
Society and culture
Bicalutamide is the generic name of the drug in English and French and its INN, USAN, USP, BAN, DCF, AAN, and JAN. It is also referred to as bicalutamidum in Latin, bicalutamida in Spanish and Portuguese, bicalutamid in German, and bikalutamid in Russian and other Slavic languages. The "-lutamide" suffix corresponds to that for NSAAs. Bicalutamide is also known by its former developmental code name ICI-176,334.
Bicalutamide is marketed by AstraZeneca in oral tablet form under the brand names Casodex, Cosudex, Calutide, Calumid, and Kalumid in many countries. It is also marketed under the brand names Bicadex, Bical, Bicalox, Bicamide, Bicatlon, Bicusan, Binabic, Bypro, Calutol, and Ormandyl among others in various countries, the drug is sold under a large number of generic trade names such as Apo-Bicalutamide, Bicalutamide Accord, Bicalutamide Actavis, Bicalutamide Bluefish, Bicalutamide Kabi, Bicalutamide Sandoz, and Bicalutamide Teva as well. A combination formulation of bicalutamide and goserelin is marketed by AstraZeneca in Australia and New Zealand under the brand name ZolaCos-CP.
Bicalutamide is a prescription drug, it is not specifically a controlled substance in any country and therefore is not an illegal drug. However, the manufacture, sale, distribution, and possession of prescription drugs are all still subject to legal regulation throughout the world.
Bicalutamide is off-patent and available as a generic, and its cost is very low in comparison to a number of other similar medications (from US$10 to US$15.44 for a 30-day supply of once-daily 50 mg tablets). Brand name Casodex costs US$556.17 for a 30-day supply of once-daily 50 mg tablets as of 2017[update]. Unlike bicalutamide, the newer NSAA enzalutamide is still on-patent, and for this reason, is far more expensive in comparison (US$7,450 for a 30-day supply as of 2015[update]).
The patent protection of all three of the first-generation NSAAs has expired and flutamide and bicalutamide are both available as relatively inexpensive generics. Nilutamide, on the other hand, has always been a poor third competitor to flutamide and bicalutamide and, in relation to this fact, has not been developed as a generic and is only available as brand name Nilandron, at least in the U.S.
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 US$10,000–$15,000 per year (or about US$1,000 per month) of treatment.
Sales and usage
|Total sales: $13.0 billion (as of end 2016)|
|* First generic availability|
Sales of bicalutamide (as Casodex) worldwide peaked at US$1.3 billion in 2007, and it has been described as a "billion-dollar-a-year" drug prior to losing its patent protection starting in 2007. 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 (mCRPC). Moreover, in spite of being off-patent, bicalutamide was said to still generate a few hundred million dollars in sales per year for AstraZeneca. Total worldwide sales of brand name Casodex were approximately US$13.0 billion as of the end of 2016.
Between January 2007 and December 2009 (a period of three years), 1,232,143 prescriptions of bicalutamide were dispensed in the U.S., 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).
A phase II clinical trial of bicalutamide with everolimus in mCRPC has been conducted. Bicalutamide has also been studied in combination with the 5α-reductase inhibitors finasteride and dutasteride in prostate cancer.
Benign prostatic hyperplasia
Bicalutamide has been studied in the treatment of benign prostatic hyperplasia (BPH) in a 24-week trial of 15 patients at a dosage of 50 mg/day. Prostate volume decreased by 26% in patients taking bicalutamide and urinary irritative symptom scores significantly decreased. Conversely, peak urine flow rates and urine pressure flow examinations were not significantly different between bicalutamide and placebo, the decrease in prostate volume achieved with bicalutamide was comparable to that observed with the 5α-reductase inhibitor finasteride, which is approved for the treatment of BPH. Breast tenderness (93%), gynecomastia (54%), and sexual dysfunction (60%) were all reported as side effects of bicalutamide at the dosage used in the study, although no treatment discontinuations due to adverse effects occurred and sexual functioning was maintained in 75% of patients.
AR-positive breast cancer
Bicalutamide has been tested for the treatment of AR-positive ER/PR-negative locally advanced and metastatic breast cancer in a phase II study for this indication. Enzalutamide is also being investigated for this type of cancer.
Bicalutamide may be used to treat hyperandrogenism and associated benign prostatic hyperplasia secondary to hyperadrenocorticism (caused by excessive adrenal androgens) in male ferrets. However, it has not been formally assessed in controlled studies for this purpose.
- Cockshott ID (2004). "Bicalutamide: clinical pharmacokinetics and metabolism". Clinical Pharmacokinetics. 43 (13): 855–878. doi:10.2165/00003088-200443130-00003. PMID 15509184.
These data indicate that direct glucuronidation is the main metabolic pathway for the rapidly cleared (S)-bicalutamide, whereas hydroxylation followed by glucuronidation is a major metabolic pathway for the slowly cleared (R)-bicalutamide.
- Finkel R, Clark MA, Cubeddu LX (2009). Pharmacology. Lippincott Williams & Wilkins. pp. 481–. ISBN 978-0-7817-7155-9.
- Sifton DW, PDR Staff (2002). PDR Drug Guide for Mental Health Professionals. Thomson/PDR. ISBN 978-1-56363-457-4.
- Lemke TL, Williams DA (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 121, 1288, 1290. ISBN 978-0-7817-6879-5. Archived from the original on 8 September 2017.
- Grosse L, Campeau AS, Caron S, Morin FA, Meunier K, Trottier J, Caron P, Verreault M, Barbier O (August 2013). "Enantiomer selective glucuronidation of the non-steroidal pure anti-androgen bicalutamide by human liver and kidney: role of the human UDP-glucuronosyltransferase (UGT)1A9 enzyme". Basic & Clinical Pharmacology & Toxicology. 113 (2): 92–102. doi:10.1111/bcpt.12071. PMC . PMID 23527766.
- Dart RC (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 497, 521. ISBN 978-0-7817-2845-4. Archived from the original on 11 May 2016.
- Dole EJ, Holdsworth MT (1997). "Nilutamide: an antiandrogen for the treatment of prostate cancer". The Annals of Pharmacotherapy. 31 (1): 65–75. doi:10.1177/106002809703100112. PMID 8997470.
page 67: Currently, information is not available regarding the activity of the major urinary metabolites of bicalutamide, bicalutamide glucuronide, and hydroxybicalutamide glucuronide.
- Schellhammer PF (September 2002). "An evaluation of bicalutamide in the treatment of prostate cancer". Expert Opinion on Pharmacotherapy. 3 (9): 1313–28. doi:10.1517/14656522.214.171.1243. PMID 12186624.
The clearance of bicalutamide occurs pre- dominantly by hepatic metabolism and glucuronidation, with excretion of the resulting inactive metabolites in the urine and faces.
- Skidmore-Roth L (17 April 2013). Mosby's 2014 Nursing Drug Reference – Elsevieron VitalSource. Elsevier Health Sciences. pp. 193–194. ISBN 978-0-323-22267-9.
- Jordan VC, Furr BJ (5 February 2010). Hormone Therapy in Breast and Prostate Cancer. Springer Science & Business Media. pp. 350–. ISBN 978-1-59259-152-7. Archived from the original on 29 May 2016.
- "Bicalutamide". The American Society of Health-System Pharmacists. Archived from the original on 29 December 2016. Retrieved 8 December 2016.
- Wass JA, Stewart PM (28 July 2011). Oxford Textbook of Endocrinology and Diabetes. OUP Oxford. pp. 1625–. ISBN 978-0-19-923529-2. Archived from the original on 11 May 2016.
- Shergill I, Arya M, Grange PR, Mundy AR (2010). Medical Therapy in Urology. Springer Science & Business Media. p. 40. ISBN 9781848827042. Archived from the original on 28 October 2014.
- Williams H, Bigby M, Diepgen T, Herxheimer A, Naldi L, Rzany B (22 January 2009). Evidence-Based Dermatology. John Wiley & Sons. pp. 529–. ISBN 978-1-4443-0017-8. Archived from the original on 2 May 2016.
- Gooren, LJ (31 March 2011). "Clinical practice. Care of transsexual persons". The New England Journal of Medicine. 364 (13): 1251–7. doi:10.1056/nejmcp1008161. PMID 21449788.
- Jameson JL, De Groot LJ (25 February 2015). Edndocrinology: Adult and Pediatric. Elsevier Health Sciences. pp. 2425–2426, 2139. ISBN 978-0-323-32195-2.
- Yuan J, Desouza R, Westney OL, Wang R (2008). "Insights of priapism mechanism and rationale treatment for recurrent priapism". Asian Journal of Andrology. 10 (1): 88–101. doi:10.1111/j.1745-7262.2008.00314.x. PMID 18087648.
- Elliott S, Latini DM, Walker LM, Wassersug R, Robinson JW (2010). "Androgen deprivation therapy for prostate cancer: recommendations to improve patient and partner quality of life". The Journal of Sexual Medicine. 7 (9): 2996–3010. doi:10.1111/j.1743-6109.2010.01902.x. PMID 20626600.
- 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.
- "Casodex® (bicalutamide) Tablets" (PDF). FDA. Archived (PDF) from the original on 27 February 2017.
- Wellington K, Keam SJ (2006). "Bicalutamide 150mg: a review of its use in the treatment of locally advanced prostate cancer" (PDF). Drugs. 66 (6): 837–50. doi:10.2165/00003495-200666060-00007. PMID 16706554. Archived (PDF) from the original on 28 August 2016.
- Lee K, Oda Y, Sakaguchi M, Yamamoto A, Nishigori C (May 2016). "Drug-induced photosensitivity to bicalutamide – case report and review of the literature". Photodermatology, Photoimmunology & Photomedicine. 32 (3): 161–4. doi:10.1111/phpp.12230. PMID 26663090.
- Lee K, et al. (2016). "Drug-induced photosensitivity to bicalutamide – case report and review of the literature". Reactions Weekly. 1612 (1): 37–37. doi:10.1007/s40278-016-19790-1.
- Singh SM, Gauthier S, Labrie F (February 2000). "Androgen receptor antagonists (antiandrogens): structure-activity relationships". Current Medicinal Chemistry. 7 (2): 211–47. doi:10.2174/0929867003375371. PMID 10637363.
- Strauss III JF, Barbieri RL (28 August 2013). Yen & Jaffe's Reproductive Endocrinology: Physiology, Pathophysiology, and Clinical Management. Elsevier Health Sciences. pp. 688–. ISBN 978-1-4557-5972-9.
Bone density improves in men receiving bicalutamide, most likely secondary to the 146% increase in estradiol and the fact that estradiol is the major mediator of bone density in men.
- Marcus R, Feldman D, Nelson D, Rosen CJ (8 November 2007). Osteoporosis. Academic Press. pp. 1354–. ISBN 978-0-08-055347-4. Archived from the original on 11 June 2016.
- Mahler C, Verhelst J, Denis L (May 1998). "Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer". Clinical Pharmacokinetics. 34 (5): 405–17. doi:10.2165/00003088-199834050-00005. PMID 9592622.
- Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 515. ISBN 9783527607495.
- "WHO Model List of Essential Medicines (19th List)" (PDF). World Health Organization. April 2015. Archived (PDF) from the original on 13 December 2016. Retrieved 8 December 2016.
- Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 381. ISBN 9781284057560.
- "Bicalutamide". International Drug Price Indicator Guide. Retrieved 8 December 2016.
- "NADAC as of 2016-12-07 | Data.Medicaid.gov". Centers for Medicare and Medicaid Services. Archived from the original on 21 December 2016. Retrieved 17 January 2017.
- "Bicalutamide – International Drug Names". Drugs.com. Archived from the original on 18 September 2016. Retrieved 13 August 2016.
- Akaza H (1999). "[A new anti-androgen, bicalutamide (Casodex), for the treatment of prostate cancer—basic clinical aspects]". Gan to Kagaku Ryoho. Cancer & Chemotherapy (in Japanese). 26 (8): 1201–7. PMID 10431591.
- "1999 Annual Report and Form 20-F" (PDF). AstraZeneca. Retrieved 1 July 2017.
- Mukherji D, Pezaro CJ, De-Bono JS (February 2012). "MDV3100 for the treatment of prostate cancer". Expert Opinion on Investigational Drugs. 21 (2): 227–33. doi:10.1517/13543784.2012.651125. PMID 22229405.
- Pchejetski D, Alshaker H, Stebbing J (2014). "Castrate-resistant prostate cancer: the future of antiandrogens". Trends in Urology & Men's Health. 5 (1): 7–10. doi:10.1002/tre.371.
- Campbell T (22 January 2014). "Slowing Sales for Johnson & Johnson's Zytiga May Be Good News for Medivation". The Motley Fool. Archived from the original on 26 August 2016. Retrieved 20 July 2016.
[...] 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, [...]
- Chang S (10 March 2010), Bicalutamide BPCA Drug Use Review in the Pediatric Population (PDF), U.S. Department of Health and Human Service, archived (PDF) from the original on 24 October 2016, retrieved 20 July 2016
- Bagatelle C, Bremner WJ (27 May 2003). Androgens in Health and Disease. Springer Science & Business Media. pp. 25–. ISBN 978-1-59259-388-0.
- 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.
- Erem C (2013). "Update on idiopathic hirsutism: diagnosis and treatment". Acta Clinica Belgica. 68 (4): 268–74. doi:10.2143/ACB.3267. PMID 24455796.
- Ascenso A, Marques HC (January 2009). "Acne in the adult". Mini Reviews in Medicinal Chemistry. 9 (1): 1–10. doi:10.2174/138955709787001730. PMID 19149656.
- Kaur S, Verma P, Sangwan A, Dayal S, Jain VK (2016). "Etiopathogenesis and Therapeutic Approach to Adult Onset Acne". Indian Journal of Dermatology. 61 (4): 403–7. doi:10.4103/0019-5154.185703. PMC . PMID 27512185.
- Lotti F, Maggi M (2015). "Hormonal Treatment for Skin Androgen-Related Disorders". European Handbook of Dermatological Treatments: 1451–1464. doi:10.1007/978-3-662-45139-7_142.
- 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
- Ho CK (December 2011). "Testosterone testing in adult males". The Malaysian Journal of Pathology. 33 (2): 71–81. PMID 22299206.
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
- Kliegman RM, Stanton B, St Geme J, Schor NF (17 April 2015). Nelson Textbook of Pediatrics. Elsevier Health Sciences. pp. 2661–. ISBN 978-0-323-26352-8.
- 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.
- Reiter EO, Mauras N, McCormick K, Kulshreshtha B, Amrhein J, De Luca F, O'Brien S, Armstrong J, Melezinkova H (October 2010). "Bicalutamide plus anastrozole for the treatment of gonadotropin-independent precocious puberty in boys with testotoxicosis: a phase II, open-label pilot study (BATT)". Journal of Pediatric Endocrinology & Metabolism. 23 (10): 999–1009. doi:10.1515/jpem.2010.161. PMID 21158211.
- Styne DM (25 April 2016). "Disorders of Puberty". Pediatric Endocrinology: A Clinical Handbook. Springer. pp. 197–. ISBN 978-3-319-18371-8.
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.
- Lenz AM, Shulman D, Eugster EA, Rahhal S, Fuqua JS, Pescovitz OH, Lewis KA (September 2010). "Bicalutamide and third-generation aromatase inhibitors in testotoxicosis". Pediatrics. 126 (3): e728–33. doi:10.1542/peds.2010-0596. PMC . PMID 20713483.
- Levey HR, Kutlu O, Bivalacqua TJ (2012). "Medical management of ischemic stuttering priapism: a contemporary review of the literature". Asian Journal of Andrology. 14 (1): 156–63. doi:10.1038/aja.2011.114. PMC . PMID 22057380.
- Broderick GA, Kadioglu A, Bivalacqua TJ, Ghanem H, Nehra A, Shamloul R (2010). "Priapism: pathogenesis, epidemiology, and management". The Journal of Sexual Medicine. 7 (1 Pt 2): 476–500. doi:10.1111/j.1743-6109.2009.01625.x. PMID 20092449.
- Chow K, Payne S (2008). "The pharmacological management of intermittent priapismic states". BJU International. 102 (11): 1515–21. doi:10.1111/j.1464-410X.2008.07951.x. PMID 18793304.
- Dahm P, Rao DS, Donatucci CF (2002). "Antiandrogens in the treatment of priapism". Urology. 59 (1): 138. doi:10.1016/S0090-4295(01)01492-3. PMID 11796309.
- Gooren LJ (2011). "Clinical review: Ethical and medical considerations of androgen deprivation treatment of sex offenders". The Journal of Clinical Endocrinology & Metabolism. 96 (12): 3628–37. doi:10.1210/jc.2011-1540. PMID 21956411.
- Giltay EJ, Gooren LJ (2009). "Potential side effects of androgen deprivation treatment in sex offenders". The Journal of the American Academy of Psychiatry and the Law. 37 (1): 53–8. PMID 19297634.
- Khan O, Mashru A (2016). "The efficacy, safety and ethics of the use of testosterone-suppressing agents in the management of sex offending". Current Opinion in Endocrinology, Diabetes and Obesity. 23 (3): 271–8. doi:10.1097/MED.0000000000000257. PMID 27032060.
- Dangerous Sex Offenders: A Task Force Report of the American Psychiatric Association. American Psychiatric Pub. 1999. pp. 111–. ISBN 978-0-89042-280-9.
- Houts FW, Taller I, Tucker DE, Berlin FS (2011). "Androgen deprivation treatment of sexual behavior". Advances in Psychosomatic Medicine. 31: 149–63. doi:10.1159/000330196. PMID 22005210.
- Rousseau L, Couture M, Dupont A, Labrie F, Couture N (1990). "Effect of combined androgen blockade with an LHRH agonist and flutamide in one severe case of male exhibitionism". The Canadian Journal of Psychiatry. 35 (4): 338–41. doi:10.1177/070674379003500412. PMID 2189544.
- "Bicalutamide Tablets, USP". Teva Pharmaceuticals USA, Inc. Archived from the original on 17 September 2016.
- Swiss Pharmaceutical Society, ed. (January 2000). Index Nominum 2000: International Drug Directory. Taylor & Francis. pp. 123–. ISBN 978-3-88763-075-1. Archived from the original on 24 April 2016.
- Sweetman SC (2011). Martindale: The Complete Drug Reference. Pharmaceutical Press. pp. 750–751. ISBN 978-0-85369-933-0.
- Suzuki H, Kamiya N, Imamoto T, Kawamura K, Yano M, Takano M, Utsumi T, Naya Y, Ichikawa T (October 2008). "Current topics and perspectives relating to hormone therapy for prostate cancer". International Journal of Clinical Oncology. 13 (5): 401–10. doi:10.1007/s10147-008-0830-y. PMID 18946750.
- White R, Bradnam V (11 March 2015). Handbook of Drug Administration via Enteral Feeding Tubes (3rd ed.). Pharmaceutical Press. pp. 133–. ISBN 978-0-85711-162-3.
- Morton I, Hall J (2001). The Avery Complete Guide to Medicines. Avery. pp. 105–106. ISBN 978-1-58333-105-7.
- Chabner BA, Longo DL (8 November 2010). Cancer Chemotherapy and Biotherapy: Principles and Practice. Lippincott Williams & Wilkins. pp. 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.
- "Zolacos CP". Drugs.com. Archived from the original on 20 September 2016.
- "Zolacos CP" (PDF). MIMS/myDr. April 2007. Archived from the original (PDF) on 17 September 2016.
- "ZOLACOS CP" (PDF). New Zealand Data Sheet. 25 July 2016. Archived (PDF) from the original on 19 September 2016.
- Skeel RT, Khleif SN (2011). Handbook of Cancer Chemotherapy. Lippincott Williams & Wilkins. pp. 724–. Archived from the original on 29 May 2016.
- Mosby's GenRx: A Comprehensive Reference for Generic and Brand Prescription Drugs. Mosby. 2001. pp. 289–290. ISBN 978-0-323-00629-3.
- PDR T (2004). Physicians' Desk Reference. Thomson PDR. ISBN 978-1-56363-471-0.
- "COSUDEX® (bicalutamide) 150 mg tablets". TGA. Archived from the original on 14 September 2016.
- Iswaran TJ, Imai M, Betton GR, Siddall RA (May 1997). "An overview of animal toxicology studies with bicalutamide (ICI 176,334)". The Journal of Toxicological Sciences. 22 (2): 75–88. doi:10.2131/jts.22.2_75. PMID 9198005.
- Smith RE (4 April 2013). Medicinal Chemistry – Fusion of Traditional and Western Medicine. Bentham Science Publishers. pp. 306–. ISBN 978-1-60805-149-6. Archived from the original on 29 May 2016.
- Sex Differences in the Human Brain, their underpinnings and implications. Elsevier. 3 December 2010. pp. 44–45. ISBN 978-0-444-53631-0. Archived from the original on 26 May 2016.
- Paoletti R (6 December 2012). Chemistry and Brain Development: Proceedings of the Advanced Study Institute on “Chemistry of Brain Development,” held in Milan, Italy, September 9–19, 1970. Springer Science & Business Media. pp. 218–. ISBN 978-1-4684-7236-3.
- Lehne RA (2013). Pharmacology for Nursing Care. Elsevier Health Sciences. pp. 1297–. ISBN 1-4377-3582-7.
- Wirth MP, Hakenberg OW, Froehner M (February 2007). "Antiandrogens in the treatment of prostate cancer". European Urology. 51 (2): 306–13; discussion 314. doi:10.1016/j.eururo.2006.08.043. PMID 17007995.
- Higano CS (February 2003). "Side effects of androgen deprivation therapy: monitoring and minimizing toxicity". Urology. 61 (2 Suppl 1): 32–8. doi:10.1016/S0090-4295(02)02397-X. PMID 12667885.
- Higano CS (2012). "Sexuality and intimacy after definitive treatment and subsequent androgen deprivation therapy for prostate cancer". Journal of Clinical Oncology. 30 (30): 3720–5. doi:10.1200/JCO.2012.41.8509. PMID 23008326.
- Kolvenbag GJ, Blackledge GR (January 1996). "Worldwide activity and safety of bicalutamide: a summary review". Urology. 47 (1A Suppl): 70–9; discussion 80–4. doi:10.1016/s0090-4295(96)80012-4. 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.
- Resnick MI, Thompson IM (2000). Advanced Therapy of Prostate Disease. PMPH-USA. pp. 379–. ISBN 978-1-55009-102-1. Archived from the original on 10 June 2016.
- Kathryn Korkidakis A, Reid RL (2017). "Testosterone in Women: Measurement and Therapeutic Use". Journal of Obstetrics and Gynaecology Canada. 39 (3): 124–130. doi:10.1016/j.jogc.2017.01.006. PMID 28343552.
- Davis SR, Wahlin-Jacobsen S (2015). "Testosterone in women--the clinical significance". The Lancet Diabetes & Endocrinology. 3 (12): 980–92. doi:10.1016/S2213-8587(15)00284-3. PMID 26358173.
- Jamnicky L, Nam R (5 November 2012). Canadian Guide to Prostate Cancer. John Wiley & Sons. pp. 177–. ISBN 978-1-118-51565-5.
- Lunglmayr G (August 1995). "Efficacy and tolerability of Casodex in patients with advanced prostate cancer. International Casodex Study Group". Anti-Cancer Drugs. 6 (4): 508–13. doi:10.1097/00001813-199508000-00003. PMID 7579554.
- McLeod DG (1997). "Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer". The Oncologist. 2 (1): 18–27. PMID 10388026.
- DeAngelis LM, Posner JB (12 September 2008). Neurologic Complications of Cancer. Oxford University Press, USA. pp. 479–. ISBN 978-0-19-971055-3. Archived from the original on 7 May 2016.
- See WA, Wirth MP, McLeod DG, Iversen P, Klimberg I, Gleason D, et al. (August 2002). "Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer: first analysis of the early prostate cancer program". The Journal of Urology. 168 (2): 429–35. doi:10.1016/S0022-5347(05)64652-6. PMID 12131282.
- Iversen P, Johansson JE, Lodding P, Lukkarinen O, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Carroll K (November 2004). "Bicalutamide (150 mg) versus placebo as immediate therapy alone or as adjuvant to therapy with curative intent for early nonmetastatic prostate cancer: 5.3-year median followup from the Scandinavian Prostate Cancer Group Study Number 6". The Journal of Urology. 172 (5 Pt 1): 1871–6. doi:10.1097/01.ju.0000139719.99825.54. PMID 15540741.
- Iversen P, Johansson JE, Lodding P, Kylmälä T, Lundmo P, Klarskov P, Tammela TL, Tasdemir I, Morris T, Armstrong J (2006). "Bicalutamide 150 mg in addition to standard care for patients with early non-metastatic prostate cancer: updated results from the Scandinavian Prostate Cancer Period Group-6 Study after a median follow-up period of 7.1 years". Scandinavian Journal of Urology and Nephrology. 40 (6): 441–52. doi:10.1080/00365590601017329. PMID 17130095.
- Hussain S, Haidar A, Bloom RE, Zayouna N, Piper MH, Jafri SM (2014). "Bicalutamide-induced hepatotoxicity: A rare adverse effect". The American Journal of Case Reports. 15: 266–70. doi:10.12659/AJCR.890679. PMC . PMID 24967002.
- Yun GY, Kim SH, Kim SW, Joo JS, Kim JS, Lee ES, Lee BS, Kang SH, Moon HS, Sung JK, Lee HY, Kim KH (April 2016). "Atypical onset of bicalutamide-induced liver injury". World Journal of Gastroenterology. 22 (15): 4062–5. doi:10.3748/wjg.v22.i15.4062. PMC . PMID 27099451.
- Dart RC (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 497–. ISBN 978-0-7817-2845-4. Archived from the original on 11 May 2016.
- Masago T, Watanabe T, Nemoto R, Motoda K (December 2011). "Interstitial pneumonitis induced by bicalutamide given for prostate cancer". International Journal of Clinical Oncology. 16 (6): 763–5. doi:10.1007/s10147-011-0239-x. PMID 21537882.
- Aronson JK (4 March 2014). Side Effects of Drugs Annual: A worldwide yearly survey of new data in adverse drug reactions. Newnes. pp. 740–. ISBN 978-0-444-62636-3. Archived from the original on 6 May 2016.
- Daba MH, El-Tahir KE, Al-Arifi MN, Gubara OA (June 2004). "Drug-induced pulmonary fibrosis". Saudi Medical Journal. 25 (6): 700–6. PMID 15195196.
- Thole Z, Manso G, Salgueiro E, Revuelta P, Hidalgo A (2004). "Hepatotoxicity induced by antiandrogens: a review of the literature". Urologia Internationalis. 73 (4): 289–95. doi:10.1159/000081585. PMID 15604569.
- Ricci F, Buzzatti G, Rubagotti A, Boccardo F (November 2014). "Safety of antiandrogen therapy for treating prostate cancer". Expert Opinion on Drug Safety. 13 (11): 1483–99. doi:10.1517/14740338.2014.966686. PMID 25270521.
- Nurse Practitioner's Drug Handbook. Springhouse Corp. 2000.
- Tyrrell CJ, Iversen P, Tammela T, Anderson J, Björk T, Kaisary AV, Morris T (September 2006). "Tolerability, efficacy and pharmacokinetics of bicalutamide 300 mg, 450 mg or 600 mg as monotherapy for patients with locally advanced or metastatic prostate cancer, compared with castration". BJU International. 98 (3): 563–72. doi:10.1111/j.1464-410X.2006.06275.x. PMID 16771791.
- Henry Winter Griffith (2008). Complete Guide to Prescription & Nonprescription Drugs 2009. HP Books. pp. 62–. ISBN 978-0-399-53463-8.
Overdose unlikely to threaten life [with NSAAs].
- Genrx (1999). 1999 Mosby's GenRx. Mosby. ISBN 978-0-323-00625-5.
A 79-year-old man attempted suicide by ingesting 13g of nilutamide (i.e., 43 times the maximum recommended dose). Despite immediate gastric lavage and oral administration of activated charcoal, plasma nilutamide levels peaked at 6 times the normal range 2 hours after ingestion. There were no clinical signs or symptoms or changes in parameters such as transaminases or chest x-ray. Maintenance treatment (150 mg/day) was resumed 30 days later.
- 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.
- Mosby's GenRx: A Comprehensive Reference for Generic and Brand Prescription Drugs. Mosby. 2001. p. 290. ISBN 978-0-323-00629-3.
In vitro studies have shown bicalutamide can displace coumarin anticoagulants, such as warfarin, from their protein-binding sites. It is recommended that if bicalutamide is started in patients already receiving coumarin anticoagulants, prothrombin times should be closely monitored and adjustment of the anticoagulant dose may be necessary.
- Spratto G, Woods A (2 July 2008). 2009 Edition Delmar's Nurse's Drug Handbook. Cengage Learning. pp. 175–. ISBN 1-4283-6106-5.
- Bohl CE, Gao W, Miller DD, Bell CE, Dalton JT (April 2005). "Structural basis for antagonism and resistance of bicalutamide in prostate cancer". Proceedings of the National Academy of Sciences of the United States of America. 102 (17): 6201–6. doi:10.1073/pnas.0500381102. PMC . PMID 15833816.
- Balaj K (25 April 2016). Managing Metastatic Prostate Cancer In Your Urological Oncology Practice. Springer. pp. 24–25. ISBN 978-3-319-31341-2. Archived from the original on 8 September 2017.
- Masiello D, Cheng S, Bubley GJ, Lu ML, Balk SP (July 2002). "Bicalutamide functions as an androgen receptor antagonist by assembly of a transcriptionally inactive receptor". The Journal of Biological Chemistry. 277 (29): 26321–6. doi:10.1074/jbc.M203310200. PMID 12015321.
- Denis L (6 December 2012). Antiandrogens in Prostate Cancer: A Key to Tailored Endocrine Treatment. Springer Science & Business Media. pp. 128, 158, 203. ISBN 978-3-642-45745-6.
- Furr BJ (June 1995). "Casodex: preclinical studies and controversies". Annals of the New York Academy of Sciences. 761 (1): 79–96. doi:10.1111/j.1749-6632.1995.tb31371.x. PMID 7625752.
- Waller AS, Sharrard RM, Berthon P, Maitland NJ (June 2000). "Androgen receptor localisation and turnover in human prostate epithelium treated with the antiandrogen, casodex". Journal of Molecular Endocrinology. 24 (3): 339–51. doi:10.1677/jme.0.0240339. PMID 10828827.
- Schellens JH, McLeod HL, Newell DR (5 May 2005). Cancer Clinical Pharmacology. OUP Oxford. pp. 229–230. ISBN 978-0-19-262966-1. Archived from the original on 10 June 2016.
- Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 1372–1373. ISBN 978-1-60913-345-0. Archived from the original on 3 May 2016.
- Butler SK, Govindan R (25 October 2010). Essential Cancer Pharmacology: The Prescriber's Guide. Lippincott Williams & Wilkins. pp. 49–. ISBN 978-1-60913-704-5.
- Becker KL (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. pp. 1119, 1196, 1208. ISBN 978-0-7817-1750-2. Archived from the original on 8 September 2017.
- Furr BJ, Tucker H (January 1996). "The preclinical development of bicalutamide: pharmacodynamics and mechanism of action". Urology. 47 (1A Suppl): 13–25; discussion 29–32. doi:10.1016/S0090-4295(96)80003-3. PMID 8560673.
- Guise TA, Oefelein MG, Eastham JA, Cookson MS, Higano CS, Smith MR (2007). "Estrogenic side effects of androgen deprivation therapy". Reviews in Urology. 9 (4): 163–80. PMC . PMID 18231613.
- Bulldan A, Malviya VN, Upmanyu N, Konrad L, Scheiner-Bobis G (2017). "Testosterone/bicalutamide antagonism at the predicted extracellular androgen binding site of ZIP9". Biochim. Biophys. Acta. 1864 (12): 2402–2414. doi:10.1016/j.bbamcr.2017.09.012. PMID 28943399.
- Thomas P, Converse A, Berg HA (2017). "ZIP9, a novel membrane androgen receptor and zinc transporter protein". Gen. Comp. Endocrinol. doi:10.1016/j.ygcen.2017.04.016. PMID 28479083.
- Pi M, Parrill AL, Quarles LD (2010). "GPRC6A mediates the non-genomic effects of steroids". J. Biol. Chem. 285 (51): 39953–64. doi:10.1074/jbc.M110.158063. PMC . PMID 20947496.
- Furr BJ (2009). "Research on reproductive medicine in the pharmaceutical industry". Human Fertility. 1 (1): 56–63. doi:10.1080/1464727982000198131. PMID 11844311.
- Figg W, Chau CH, Small EJ (14 September 2010). Drug Management of Prostate Cancer. Springer Science & Business Media. pp. 56, 71–72, 75, 93. ISBN 978-1-60327-829-4.
- Furr BJ (1996). "The development of Casodex (bicalutamide): preclinical studies". European Urology. 29 Suppl 2: 83–95. PMID 8717469.
- Chapple CR, Steers WD (10 May 2011). Practical Urology: Essential Principles and Practice: Essential Principles and Practice. Springer Science & Business Media. pp. 225–. ISBN 978-1-84882-034-0.
Normal reference ranges for serum total testosterone in adult men is generally considered to be 300–1,000 ng/dL (10–35 nmol/L).
- Gentile V, Panebianco V, Sciarra A (11 April 2014). Multidisciplinary Management of Prostate Cancer: The Role of the Prostate Cancer Unit. Springer Science & Business Media. pp. 106–. ISBN 978-3-319-04385-2.
The standard castrate level is <50 ng/dl. It was defined more than 40 years ago, when testosterone level testing was limited. However, current testing methods using chemiluminescence have found that the mean value of testosterone after surgical castration is 15 ng/dL.
- Denis L, Mahler C (January 1996). "Pharmacodynamics and pharmacokinetics of bicalutamide: defining an active dosing regimen". Urology. 47 (1A Suppl): 26–8; discussion 29–32. doi:10.1016/S0090-4295(96)80004-5. PMID 8560674.
- Boccardo F, Rubagotti A, Conti G, Potenzoni D, Manganelli A, Del Monaco D (2005). "Exploratory study of drug plasma levels during bicalutamide 150 mg therapy co-administered with tamoxifen or anastrozole for prophylaxis of gynecomastia and breast pain in men with prostate cancer" (PDF). Cancer Chemotherapy and Pharmacology. 56 (4): 415–20. doi:10.1007/s00280-005-1016-1. PMID 15838655.
- Chung LW, Isaacs WB, Simons JW (10 November 2007). Prostate Cancer: Biology, Genetics, and the New Therapeutics. Springer Science & Business Media. pp. 365–. ISBN 978-1-59745-224-3. Archived from the original on 20 May 2016.
- Melmed S, Polonsky KS, Reed Larsen P, Kronenberg HM (30 November 2015). Williams Textbook of Endocrinology. Elsevier Health Sciences. pp. 704–708, 711, 1104. ISBN 978-0-323-29738-7.
- Bruskewitz R (6 December 2012). Atlas of the Prostate. Springer Science & Business Media. pp. 5,190. ISBN 978-1-4615-6505-5.
- Nieschlag E, Behre HM (6 December 2012). Testosterone: Action – Deficiency – Substitution. Springer Science & Business Media. pp. 130, 276. ISBN 978-3-642-72185-4.
- Mozayani A, Raymon L (18 September 2011). Handbook of Drug Interactions: A Clinical and Forensic Guide. Springer Science & Business Media. pp. 656–. ISBN 978-1-61779-222-9.
- Mydlo JH, Godec CJ (29 September 2015). Prostate Cancer: Science and Clinical Practice. Elsevier Science. pp. 516–521, 534–540. ISBN 978-0-12-800592-7. Archived from the original on 8 September 2017.
- Luo S, Martel C, Chen C, Labrie C, Candas B, Singh SM, Labrie F (December 1997). "Daily dosing with flutamide or Casodex exerts maximal antiandrogenic activity". Urology. 50 (6): 913–9. doi:10.1016/S0090-4295(97)00393-2. PMID 9426723.
- Diamanti-Kandarakis E, Nestler JE, Pandas D, Pasquale R (21 December 2009). Insulin Resistance and Polycystic Ovarian Syndrome: Pathogenesis, Evaluation, and Treatment. Springer Science & Business Media. pp. 75–. ISBN 978-1-59745-310-3. Archived from the original on 19 May 2016.
- Carrell DT, Peterson CM (23 March 2010). Reproductive Endocrinology and Infertility: Integrating Modern Clinical and Laboratory Practice. Springer Science & Business Media. pp. 163–. ISBN 978-1-4419-1436-1. Archived from the original on 4 July 2014.
- Bouchard P, Caraty A (15 November 1993). GnRH, GnRH Analogs, Gonadotropins and Gonadal Peptides. CRC Press. pp. 455–456. ISBN 978-0-203-09205-7.
[...] when male levels of androgens are achieved in plasma, their effects on gonadotropin secretion are similar in women and men. [...] administration of flutamide in a group of normally-cycling women produced a clinical improvement of acne and hirsutism without any significant hormonal change. [...] All these data emphasize that physiological levels of androgens have no action on the regulation of gonadotropins in normal women. [...] Androgens do not directly play a role in gonadotropin regulation [in women].
- Costanzo Giulio Moretti, Laura Guccione, Paola Di Giacinto, Amalia Cannuccia, Chiara Meleca, Giulia Lanzolla, Aikaterini Andreadi, Davide Lauro (2016), Efficacy and Safety of Myo-Inositol Supplementation in the Treatment of Obese Hirsute PCOS Women: Comparative Evaluation with OCP+Bicalutamide Therapy, doi:10.1210/endo-meetings.2016.RE.5.SUN-153
- Fradet Y (February 2004). "Bicalutamide (Casodex) in the treatment of prostate cancer". Expert Review of Anticancer Therapy. 4 (1): 37–48. doi:10.1586/14737126.96.36.199. PMID 14748655.
In contrast, the incidence of diarrhea was comparable between the bicalutamide and placebo groups (6.3 vs. 6.4%, respectively) in the EPC program .
- Iversen P, Melezinek I, Schmidt A (January 2001). "Nonsteroidal antiandrogens: a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function". BJU International. 87 (1): 47–56. doi:10.1046/j.1464-410x.2001.00988.x. PMID 11121992.
- DeVita Jr VT, Lawrence TS, Rosenberg SA (7 January 2015). DeVita, Hellman, and Rosenberg's Cancer: Principles & Practice of Oncology. Wolters Kluwer Health. pp. 1142–. ISBN 978-1-4698-9455-3.
- Eri LM, Haug E, Tveter KJ (March 1995). "Effects on the endocrine system of long-term treatment with the non-steroidal anti-androgen Casodex in patients with benign prostatic hyperplasia". British Journal of Urology. 75 (3): 335–40. doi:10.1111/j.1464-410X.1995.tb07345.x. PMID 7537602.
- Wein AJ, Kavoussi LR, Novick AC, Partin AW, Peters CA (25 August 2011). Campbell-Walsh Urology: Expert Consult Premium Edition: Enhanced Online Features and Print, 4-Volume Set. Elsevier Health Sciences. pp. 2938–2939, 2946. ISBN 978-1-4160-6911-9. Archived from the original on 5 May 2016.
- Lunglmayr G (1989). "Casodex (ICI 176,334), a new, non-steroidal anti-androgen. Early clinical results". Hormone Research. 32 Suppl 1: 77–81. doi:10.1159/000181316. PMID 2515147.
- 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. Archived from the original on 25 July 2014.
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.
- Bach PV, Najari BB, Kashanian JA (2016). "Adjunct Management of Male Hypogonadism". Current Sexual Health Reports. doi:10.1007/s11930-016-0089-7. ISSN 1548-3584.
- Santen RJ, Leonard JM, Sherins RJ, Gandy HM, Paulsen CA (1971). "Short- and long-term effects of clomiphene citrate on the pituitary-testicular axis". J. Clin. Endocrinol. Metab. 33 (6): 970–9. doi:10.1210/jcem-33-6-970. PMID 5135636.
Increase in serum LH levels ranged from 200–700% during the initial 21 days of clomiphene administration but then plateaued. Serum FSH levels exhibited a similar plateau after 35 days, with maximum titers 70–360% over control, the range in serum testosterone increments after 7 and 51 days of clomiphene administration was similar to that observed in serum gonadotrophin levels.
- Martini L (2 December 2012). Clinical Neuroendocrinology. Elsevier. p. 239. ISBN 978-0-323-14429-2.
From the studies of Santen et al. (1971), it seems that a longer period of administration (51 days in their study) would cause an even greater rise in FSH and LH (70–360% and 200–700%, respectively).
- Sieber PR (December 2007). "Treatment of bicalutamide-induced breast events". Expert Review of Anticancer Therapy. 7 (12): 1773–9. doi:10.1586/14737188.8.131.523. PMID 18062751.
- Wibowo E, Schellhammer P, Wassersug RJ (January 2011). "Role of estrogen in normal male function: clinical implications for patients with prostate cancer on androgen deprivation therapy". The Journal of Urology. 185 (1): 17–23. doi:10.1016/j.juro.2010.08.094. PMID 21074215.
- Motofei IG, Rowland DL, Popa F, Kreienkamp D, Paunica S (July 2011). "Preliminary study with bicalutamide in heterosexual and homosexual patients with prostate cancer: a possible implication of androgens in male homosexual arousal". BJU International. 108 (1): 110–5. doi:10.1111/j.1464-410X.2010.09764.x. PMID 20955264.
- Wibowo E, Wassersug RJ (September 2013). "The effect of estrogen on the sexual interest of castrated males: Implications to prostate cancer patients on androgen-deprivation therapy". Critical Reviews in Oncology/Hematology. 87 (3): 224–38. doi:10.1016/j.critrevonc.2013.01.006. PMID 23484454.
- Simpson ER, Jones ME (2007). "Of mice and men: the many guises of estrogens". Ernst Schering Foundation Symposium Proceedings. 2006/1 (1): 45–67. doi:10.1007/2789_2006_016. PMID 17824171.
- King SR (2008). "Emerging roles for neurosteroids in sexual behavior and function". Journal of Andrology. 29 (5): 524–33. doi:10.2164/jandrol.108.005660. PMID 18567641.
- Morali G, Oropeza MV, Lemus AE, Perez-Palacios G (September 1994). "Mechanisms regulating male sexual behavior in the rat: role of 3 alpha- and 3 beta-androstanediols". Biology of Reproduction. 51 (3): 562–71. doi:10.1095/biolreprod51.3.562. PMID 7803627.
- Sánchez Montoya EL, Hernández L, Barreto-Estrada JL, Ortiz JG, Jorge JC (November 2010). "The testosterone metabolite 3α-diol enhances female rat sexual motivation when infused in the nucleus accumbens shell". The Journal of Sexual Medicine. 7 (11): 3598–609. doi:10.1111/j.1743-6109.2010.01937.x. PMC . PMID 20646182.
- Chedrese PJ (13 June 2009). Reproductive Endocrinology: A Molecular Approach. Springer Science & Business Media. pp. 233–. ISBN 978-0-387-88186-7. Archived from the original on 5 September 2017.
- Frye CA, Edinger KL, Lephart ED, Walf AA (2010). "3alpha-androstanediol, but not testosterone, attenuates age-related decrements in cognitive, anxiety, and depressive behavior of male rats". Frontiers in Aging Neuroscience. 2: 15. doi:10.3389/fnagi.2010.00015. PMC . PMID 20552051.
- Huang Q, Zhu H, Fischer DF, Zhou JN (June 2008). "An estrogenic effect of 5alpha-androstane-3beta, 17beta-diol on the behavioral response to stress and on CRH regulation". Neuropharmacology. 54 (8): 1233–8. doi:10.1016/j.neuropharm.2008.03.016. PMID 18457850.
- Frye CA, Koonce CJ, Edinger KL, Osborne DM, Walf AA (November 2008). "Androgens with activity at estrogen receptor beta have anxiolytic and cognitive-enhancing effects in male rats and mice". Hormones and Behavior. 54 (5): 726–34. doi:10.1016/j.yhbeh.2008.07.013. PMC . PMID 18775724.
- Bambury RM, Scher HI (June 2015). "Enzalutamide: Development from bench to bedside". Urologic Oncology. 33 (6): 280–8. doi:10.1016/j.urolonc.2014.12.017. PMID 25797385.
- Bambury RM, Rathkopf DE (August 2016). "Novel and next-generation androgen receptor-directed therapies for prostate cancer: Beyond abiraterone and enzalutamide". Urologic Oncology. 34 (8): 348–55. doi:10.1016/j.urolonc.2015.05.025. PMID 26162486.
- Pinto Á (February 2014). "Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer". Cancer Biology & Therapy. 15 (2): 149–55. doi:10.4161/cbt.26724. PMC . PMID 24100689.
- Orentreich N, Durr NP (1974). "Mammogenesis in Transsexuals". Journal of Investigative Dermatology. 63 (1): 142–6. doi:10.1111/1523-1747.ep12678272. PMID 4365991.
- Strauss III JF, Barbieri RL (13 September 2013). Yen and Jaffe's Reproductive Endocrinology. Elsevier Health Sciences. pp. 236–237. ISBN 978-1-4557-2758-2. Archived from the original on 14 January 2017.
- Wilson CB, Nizet V, Maldonado Y, Klein JO, Remington JS (2015). Remington and Klein's Infectious Diseases of the Fetus and Newborn Infant. Elsevier Health Sciences. pp. 190–. ISBN 978-0-323-24147-2. Archived from the original on 14 January 2017.
- Yen SS, Jaffe RB, Barbieri RL (2001). Endocrinología de la reproducción: fisiología, fisiopatología y manejo clínico. Ed. Medic Panamericana. pp. 303–. ISBN 978-950-06-2538-8.
- Pinsky L, Ericsson RP, Schimke RN (1999). Genetic Disorders of Human Sexual Development. Oxford University Press. pp. 215–. ISBN 978-0-19-510907-8.
- Wassersug RJ, Oliffe JL (April 2009). "The social context for psychological distress from iatrogenic gynecomastia with suggestions for its management". The Journal of Sexual Medicine. 6 (4): 989–1000. doi:10.1111/j.1743-6109.2008.01053.x. PMID 19175864.
By themselves, the LH-RH agonists do not produce much gynecomastia (ie, estimates as low as 4.4%) , but in conjunction with the typically prescribed antiandrogens (flutamide, bicalutamide, and nilutamide), gynecomastia is more common (49–68%) .
- Kanhai RC, Hage JJ, van Diest PJ, Bloemena E, Mulder JW (January 2000). "Short-term and long-term histologic effects of castration and estrogen treatment on breast tissue of 14 male-to-female transsexuals in comparison with two chemically castrated men". The American Journal of Surgical Pathology. 24 (1): 74–80. doi:10.1097/00000478-200001000-00009. PMID 10632490.
- Lawrence AA (2006). "Transgender Health Concerns". In Meyer IH, Northridge ME. The Health of Sexual Minorities Public Health Perspectives on Lesbian, Gay, Bisexual and Transgender Populations. New York: Springer. p. 476. doi:10.1007/978-0-387-31334-4_19. ISBN 978-0-387-28871-0.
- Rosen PP (2009). Rosen's Breast Pathology (3 ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 31–. ISBN 978-0-7817-7137-5.
- Lorincz AM, Sukumar S (2006). "Molecular links between obesity and breast cancer". Endocrine-related Cancer. 13 (2): 279–92. doi:10.1677/erc.1.00729. PMID 16728564.
Adipocytes make up the bulk of the human breast, with epithelial cells accounting for only approximately 10% of human breast volume.
- Howard BA, Gusterson BA (2000). "Human breast development". Journal of Mammary Gland Biology and Neoplasia. 5 (2): 119–37. PMID 11149569.
In the stroma, there is an increase in the amount of fibrous and fatty tissue, with the adult nonlactating breast consisting of 80% or more of stroma.
- Sperling MA (10 April 2014). Pediatric Endocrinology. Elsevier Health Sciences. pp. 598–. ISBN 978-1-4557-5973-6.
Estrogen stimulates the nipples to grow, mammary terminal duct branching to progress to the stage at which ductules are formed, and fatty stromal growth to increase until it constitutes about 85% of the mass of the breast. [...] Lobulation appears around menarche, when multiple blind saccular buds form by branching of the terminal ducts. These effects are due to the presence of progesterone. [...] Full alveolar development normally only occurs during pregnancy under the influence of additional progesterone and prolactin.
- Hagisawa S, Shimura N, Arisaka O (2012). "Effect of excess estrogen on breast and external genitalia development in growth hormone deficiency". Journal of Pediatric and Adolescent Gynecology. 25 (3): e61–3. doi:10.1016/j.jpag.2011.11.005. PMID 22206682.
Estrogen stimulates growth of the nipples, progression of mammary duct branching to the stage at which ductiles are formed, and fatty stromal growth until it constitutes about 85% of the mass of the breast.
- J. Aiman (6 December 2012). Infertility: Diagnosis and Management. Springer Science & Business Media. pp. 182–. ISBN 978-1-4613-8265-2.
- Kroemer RW (2009). The Reproductive System. Infobase Publishing. pp. 51–. ISBN 978-1-4381-3083-5.
- Fody EP, Walker EM (1985). "Effects of drugs on the male and female reproductive systems". Ann. Clin. Lab. Sci. 15 (6): 451–8. PMID 4062226.
- Liu YX (2005). "Control of spermatogenesis in primate and prospect of male contraception". Arch. Androl. 51 (2): 77–92. doi:10.1080/01485010490485768. PMID 15804862.
- Cheng CY, Wong EW, Yan HH, Mruk DD (2010). "Regulation of spermatogenesis in the microenvironment of the seminiferous epithelium: new insights and advances". Mol. Cell. Endocrinol. 315 (1–2): 49–56. doi:10.1016/j.mce.2009.08.004. PMC . PMID 19682538.
- Schill W, Comhaire FH, Hargreave TB (26 August 2006). Andrology for the Clinician. Springer Science & Business Media. pp. 76–. ISBN 978-3-540-33713-3. Archived from the original on 26 May 2016.
- Cheng C (24 October 2009). Molecular Mechanisms in Spermatogenesis. Springer Science & Business Media. pp. 258–. ISBN 978-0-387-09597-4.
- Morgante E, Gradini R, Realacci M, Sale P, D'Eramo G, Perrone GA, Cardillo MR, Petrangeli E, Russo M, Di Silverio F (March 2001). "Effects of long-term treatment with the anti-androgen bicalutamide on human testis: an ultrastructural and morphometric study". Histopathology. 38 (3): 195–201. doi:10.1046/j.1365-2559.2001.01077.x. PMID 11260298.
- Johnson LR (14 October 2003). Essential Medical Physiology. Academic Press. pp. 731–. ISBN 978-0-08-047270-6. Archived from the original on 15 February 2017.
- Mulhall JP (21 February 2013). Fertility Preservation in Male Cancer Patients. Cambridge University Press. pp. 84–. ISBN 978-1-139-61952-3. Archived from the original on 29 April 2016.
- Khursheed A, Minhas LA, Diaz WA (September 2011). "Histomorphometric study of effects of bicalutamide on spermatogenesis in male rats" (PDF). Pakistan Armed Forces Medical Journal (3). Archived (PDF) from the original on 23 June 2016.
- Dohle GR, Smit M, Weber RF (November 2003). "Androgens and male fertility". World Journal of Urology. 21 (5): 341–5. doi:10.1007/s00345-003-0365-9. PMID 14566423.
- Basu SC (15 December 2011). Male Reproductive Dysfunction. Jaypee Brothers Medical Publishers Pvt. Ltd. pp. 323–. ISBN 978-93-5025-703-6.
- Jones CA, Reiter L, Greenblatt E (2016). "Fertility preservation in transgender patients". International Journal of Transgenderism. 17 (2): 76–82. doi:10.1080/15532739.2016.1153992. ISSN 1553-2739.
Traditionally, patients have been advised to cryopreserve sperm prior to starting cross-sex hormone therapy as there is a potential for a decline in sperm motility with high-dose estrogen therapy over time (Lubbert et al., 1992). However, this decline in fertility due to estrogen therapy is controversial due to limited studies.
- Payne AH, Hardy MP (28 October 2007). The Leydig Cell in Health and Disease. Springer Science & Business Media. pp. 422–431. ISBN 978-1-59745-453-7.
Estrogens are highly efficient inhibitors of the hypothalamic-hypophyseal-testicular axis (212–214). Aside from their negative feedback action at the level of the hypothalamus and pituitary, direct inhibitory effects on the testis are likely (215,216). [...] The histology of the testes [with estrogen treatment] showed disorganization of the seminiferous tubules, vacuolization and absence of lumen, and compartmentalization of spermatogenesis.
- Wakelin SH, Maibach HI, Archer CB (1 June 2002). Systemic Drug Treatment in Dermatology: A Handbook. CRC Press. pp. 32–. ISBN 978-1-84076-013-2. Archived from the original on 25 July 2014.
[Cyproterone acetate] inhibits spermatogenesis and produces reversible infertility (but is not a male contraceptive).
- Neumann F (1994). "The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic research". Exp. Clin. Endocrinol. 102 (1): 1–32. doi:10.1055/s-0029-1211261. PMID 8005205.
Spermatogenesis is also androgen-dependent and is inhibited by CPA, meaning that patients treated with high doses of CPA are sterile (Figure 23). All the effects of CPA are fully reversible.
- Salam MA (2003). Principles & Practice of Urology: A Comprehensive Text. Universal-Publishers. pp. 684–. ISBN 978-1-58112-412-5.
Estrogens act primarily through negative feedback at the hypothalamic-pituitary level to reduce LH secretion and testicular androgen synthesis. [...] Interestingly, if the treatment with estrogens is discontinued after 3 yr. of uninterrupted exposure, serum testosterone may remain at castration levels for up to another 3 yr. This prolonged suppression is thought to result from a direct effect of estrogens on the Leydig cells.
- Mast N, Lin JB, Pikuleva IA (September 2015). "Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy". Molecular Pharmacology. 88 (3): 428–36. doi:10.1124/mol.115.099598. PMC . PMID 26082378.
- Mast N, Zheng W, Stout CD, Pikuleva IA (February 2013). "Binding of a cyano- and fluoro-containing drug bicalutamide to cytochrome P450 46A1: unusual features and spectral response". The Journal of Biological Chemistry. 288 (7): 4613–24. doi:10.1074/jbc.M112.438754. PMC . PMID 23288837.
- Zhu Y, Liu C, Armstrong C, Lou W, Sandher A, Gao AC (September 2015). "Antiandrogens Inhibit ABCB1 Efflux and ATPase Activity and Reverse Docetaxel Resistance in Advanced Prostate Cancer". Clinical Cancer Research. 21 (18): 4133–42. doi:10.1158/1078-0432.CCR-15-0269. PMC . PMID 25995342.
- Fenner A (July 2015). "Prostate cancer: Antiandrogens reverse docetaxel resistance via ABCB1 inhibition". Nature Reviews. Urology. 12 (7): 361. doi:10.1038/nrurol.2015.135. PMID 26057062.
- Armstrong CM, Gao AC (2015). "Drug resistance in castration resistant prostate cancer: resistance mechanisms and emerging treatment strategies". American Journal of Clinical and Experimental Urology. 3 (2): 64–76. PMC . PMID 26309896.
- Foster WR, Car BD, Shi H, Levesque PC, Obermeier MT, Gan J, Arezzo JC, Powlin SS, Dinchuk JE, Balog A, Salvati ME, Attar RM, Gottardis MM (April 2011). "Drug safety is a barrier to the discovery and development of new androgen receptor antagonists". The Prostate. 71 (5): 480–8. doi:10.1002/pros.21263. PMID 20878947.
- Barrish J, Carter P, Cheng P (2010). Accounts in Drug Discovery: Case Studies in Medicinal Chemistry. Royal Society of Chemistry. pp. 127–. ISBN 978-1-84973-126-3.
- Kolvenbag GJ, Blackledge GR, Gotting-Smith K (January 1998). "Bicalutamide (Casodex) in the treatment of prostate cancer: history of clinical development". The Prostate. 34 (1): 61–72. doi:10.1002/(SICI)1097-0045(19980101)34:1<61::AID-PROS8>3.0.CO;2-N. PMID 9428389.
- Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". European Urology. 29 Suppl 2: 96–104. PMID 8717470.
Casodex is associated with significantly less gastrointestinal effects (diarrhoea) than the nonsteroidal antiandrogen flutamide (Eulexin, Schering-Plough International). Casodex is not associated with alcohol intolerance, pneumonitis and ocular defects which have been seen with the antiandrogen nilutamide (Anandron, Roussel).
- Chu E, DeVita Jr VT (28 December 2012). Physicians' Cancer Chemotherapy Drug Manual 2013. Jones & Bartlett Publishers. pp. 51–. ISBN 978-1-284-04039-5.
- Bunce CM, Campbell MJ (11 March 2010). Nuclear Receptors: Current Concepts and Future Challenges. Springer Science & Business Media. pp. 160, 167. ISBN 978-90-481-3303-1. Archived from the original on 10 June 2016.
- Beale C, Collins P (15 May 1996). The Cardioprotective Role of HRT: A Clinical Update. CRC Press. pp. 14–. ISBN 978-1-85070-740-0.
- Helsen C, Van den Broeck T, Voet A, Prekovic S, Van Poppel H, Joniau S, Claessens F (August 2014). "Androgen receptor antagonists for prostate cancer therapy". Endocrine-Related Cancer. 21 (4): T105–18. doi:10.1530/ERC-13-0545. PMID 24639562.
- Furr BJ (1989). ""Casodex" (ICI 176,334)--a new, pure, peripherally-selective anti-androgen: preclinical studies". Hormone Research. 32 Suppl 1 (1): 69–76. doi:10.1159/000181315. PMID 2533159.
- Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen". The Journal of Endocrinology. 113 (3): R7–9. doi:10.1677/joe.0.113R007. PMID 3625091.
- Soloway MS, Schellhammer PF, Smith JA, Chodak GW, Vogelzang NJ, Kennealey GT (December 1995). "Bicalutamide in the treatment of advanced prostatic carcinoma: a phase II noncomparative multicenter trial evaluating safety, efficacy and long-term endocrine effects of monotherapy". The Journal of Urology. 154 (6): 2110–4. doi:10.1016/S0022-5347(01)66709-0. PMID 7500470.
- Gao W, Dalton JT (March 2007). "Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs)". Drug Discovery Today. 12 (5–6): 241–8. doi:10.1016/j.drudis.2007.01.003. PMC . PMID 17331889.
- Mason M (August 2006). "What implications do the tolerability profiles of antiandrogens and other commonly used prostate cancer treatments have on patient care?". Journal of Cancer Research and Clinical Oncology. 132 Suppl 1: S27–35. doi:10.1007/s00432-006-0134-4. PMID 16896883.
- Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (2015). "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Scientific Reports. 5: 12007. doi:10.1038/srep12007. PMC . PMID 26137992.
- Anderson PO, Knoben JE, Troutman WG (22 August 2001). Handbook of Clinical Drug Data. McGraw Hill Professional. p. 245. ISBN 978-0-07-138942-6.
With an oral dose of 50 mg/day, bicalutamide attains a peak serum level of 8.9 mg/L (21 μmol/L) 31 hr after a dose at steady state. CI of (R)-bicalutamide is 0.32 L/hr. The active (R)-enantiomer of bicalutamide is oxidized to an inactive metabolite, which, like the inactive (S)-enantiomer, is glucuronidated and cleared rapidly by elimination in the urine and feces.165
- Sharma K, Pawar GV, Giri S, Rajagopal S, Mullangi R (2012). "Development and validation of a highly sensitive LC-MS/MS-ESI method for the determination of bicalutamide in mouse plasma: application to a pharmacokinetic study". Biomedical Chromatography. 26 (12): 1589–95. doi:10.1002/bmc.2736. PMID 22495777.
- McPherson EM (22 October 2013). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). William Andrew Publishing. pp. 627, 1695. ISBN 978-0-8155-1856-3. Archived from the original on 9 June 2016.
- Komsta L, Waksmundzka-Hajnos M, Sherma J (20 December 2013). Thin Layer Chromatography in Drug Analysis. CRC Press. pp. 652–. ISBN 978-1-4665-0715-9.
- Sancheti PP, Vyas VM, Shah M, Karekar P, Pore YV (2008). "Spectrophotometric estimation of bicalutamide in tablets". Indian Journal of Pharmaceutical Sciences. 70 (6): 810–2. doi:10.4103/0250-474X.49131. PMC . PMID 21369450.
- Mohler ML, Bohl CE, Jones A, Coss CC, Narayanan R, He Y, Hwang DJ, Dalton JT, Miller DD (June 2009). "Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit". Journal of Medicinal Chemistry. 52 (12): 3597–617. doi:10.1021/jm900280m. PMID 19432422.
[C]linically relevant antiandrogens currently are nonsteroidal anilide derivatives. Antiandrogens used for prostate cancer include the monoarylpropionamide flutamide (1) (a prodrug of hydroxyflutamide (2)),29–31 the hydantoin nilutamide(3),32–34 and the diarylpropionamide bicalutamide (4) (Chart1).35–37
- Bégué J, Bonnet-Delpon D (2 June 2008). Bioorganic and Medicinal Chemistry of Fluorine. John Wiley & Sons. pp. 327–. ISBN 978-0-470-28187-1.
- Ball AL, Kamalian L, Alfirevic A, Lyon JJ, Chadwick AE (July 2016). "Identification of the Additional Mitochondrial Liabilities of 2-Hydroxyflutamide When Compared With its Parent Compound, Flutamide in HepG2 Cells". Toxicological Sciences: kfw126. doi:10.1093/toxsci/kfw126. PMID 27413113.
- Hermkens PH, Kamp S, Lusher S, Veeneman GH (July 2006). "Non-steroidal steroid receptor modulators". IDrugs. 9 (7): 488–94. PMID 16821162.
- Avram MR, Rogers NE (30 November 2009). Hair Transplantation. Cambridge University Press. pp. 11–. ISBN 978-1-139-48339-1.
- Haber RS, Stough DB (2006). Hair Transplantation. Elsevier Health Sciences. pp. 6–7. ISBN 978-1-4160-3104-8. Archived from the original on 4 July 2014. Retrieved 28 May 2012.
- Kawahara T, Minamoto H (2014). "Androgen Receptor Antagonists in the Treatment of Prostate Cancer". Clinical Immunology, Endocrine & Metabolic Drugs. 1 (1): 11–19. doi:10.2174/22127070114019990002.
- Moilanen AM, Riikonen R, Oksala R, Ravanti L, Aho E, Wohlfahrt G, Nykänen PS, Törmäkangas OP, Palvimo JJ, Kallio PJ (2015). "Discovery of ODM-201, a new-generation androgen receptor inhibitor targeting resistance mechanisms to androgen signaling-directed prostate cancer therapies". Sci Rep. 5: 12007. doi:10.1038/srep12007. PMC . PMID 26137992.
- Segal S, Narayanan R, Dalton JT (April 2006). "Therapeutic potential of the SARMs: revisiting the androgen receptor for drug discovery". Expert Opinion on Investigational Drugs. 15 (4): 377–87. doi:10.1517/135437184.108.40.2067. PMID 16548787.
Structural modifications of bicalutamide led to the discovery of the first nonsteroidal androgens (the aryl propionamides) in 1998. Lead compounds in this class (denoted S1 and S4 in published literature) not only bind to the AR with high affinity (low nanomolar range), but also demonstrate tissue selectivity in animal models [46,50].
- Yin D, Gao W, Kearbey JD, Xu H, Chung K, He Y, Marhefka CA, Veverka KA, Miller DD, Dalton JT (March 2003). "Pharmacodynamics of selective androgen receptor modulators". The Journal of Pharmacology and Experimental Therapeutics. 304 (3): 1334–40. doi:10.1124/jpet.102.040840. PMC . PMID 12604714.
- Ottow E, Weinmann H (8 September 2008). Nuclear Receptors as Drug Targets. John Wiley & Sons. pp. 257–258. ISBN 978-3-527-62330-3.
- Parent EE, Dence CS, Jenks C, Sharp TL, Welch MJ, Katzenellenbogen JA (2007). "Synthesis and biological evaluation of [18F]bicalutamide, 4-[76Br]bromobicalutamide, and 4-[76Br]bromo-thiobicalutamide as non-steroidal androgens for prostate cancer imaging". J. Med. Chem. 50 (5): 1028–40. doi:10.1021/jm060847r. PMID 17328524.
- Dierckx RA, Otte A, de Vries EF, van Waarde A, Luiten PG (15 February 2014). PET and SPECT of Neurobiological Systems. Springer Science & Business Media. pp. 394–. ISBN 978-3-642-42014-6.
- de Jesus Cortez F, Nguyen P, Truillet C, Tian B, Kuchenbecker KM, Evans MJ, Webb P, Jacobson MP, Fletterick RJ, England PM (2017). "Development of 5N-Bicalutamide, a High-Affinity Reversible Covalent Antiandrogen". ACS Chem. Biol. doi:10.1021/acschembio.7b00702. PMID 28981251.
- Pamela, M., Fletterick, R. J., Kuchenbecker, K., & de Jesus Cortez, F. (2016). U.S. Patent Application No. 15/382,942. https://www.google.com/patents/US20170101384
- Tucker H, Crook JW, Chesterson GJ (1988). "Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides". Journal of Medicinal Chemistry. 31 (5): 954–9. doi:10.1021/jm00400a011. PMID 3361581.
- James KD, Ekwuribe NN (2002). "A Two-step Synthesis of the Anti-cancer Drug (R,S)-Bicalutamide". Synthesis. 2002 (7): 850–2. doi:10.1055/s-2002-28508.
- US application 2006/0041161, Pizzetti E, Vigano E, Lussana M, Landonio E, "Procedure for the synthesis of bicalutamide", published 23 February 2006
- Chand M, Shukla AK (2012). "Novel Synthesis of Bicalutamide Drug Substance and their Impurities using Imidazolium Type of Ionic Liquid". SSRN Electronic Journal. doi:10.2139/ssrn.2160199.
- Diamanti-Kandarakis E (September 1999). "Current aspects of antiandrogen therapy in women". Current Pharmaceutical Design. 5 (9): 707–23. PMID 10495361.
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 .
- Denis LJ, Griffiths K, Kaisary AV, Murphy GP (1 March 1999). Textbook of Prostate Cancer: Pathology, Diagnosis and Treatment: Pathology, Diagnosis and Treatment. CRC Press. pp. 55,279–280. ISBN 978-1-85317-422-3. Archived from the original on 3 June 2016.
- Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 573–. ISBN 978-1-4757-2085-3. Archived from the original on 15 May 2016.
- Cadilla R, Turnbull P (2006). "Selective androgen receptor modulators in drug discovery: medicinal chemistry and therapeutic potential". Curr Top Med Chem. 6 (3): 245–70. doi:10.2174/156802606776173456. PMID 16515480.
- Engel J, Kleemann A, Kutscher B, Reichert D (2009). Pharmaceutical Substances: Syntheses, Patents and Applications of the most relevant APIs (5th ed.). Thieme. pp. 153–154. ISBN 978-3-13-179275-4.
- Furr BJ, Valcaccia B, Curry B, Woodburn JR, Chesterson G, Tucker H (June 1987). "ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen". The Journal of Endocrinology. 113 (3): R7–9. doi:10.1677/joe.0.113r007. PMID 3625091.
- Newling DW (1990). "The response of advanced prostatic cancer to a new non-steroidal antiandrogen: results of a multicenter open phase II study of Casodex. European/Australian Co-operative Group". European Urology. 18 Suppl 3: 18–21. PMID 2094607.
- The United States Patents Quarterly. Associated Industry Publications. 1997.
- Chaurasiya A, Singh AK, Upadhyay SC, Asati D, Ahmad FJ, Mukherjee R, Khar RK (2012). "Lipidic Nanocarrier for Oral Bioavailability Enhancement of an Anticancer Agent: Formulation Design and Evaluation". Advanced Science Letters. 11 (1): 43–52. doi:10.1166/asl.2012.2170. ISSN 1936-6612.
- 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.
- Gohil K (August 2015). "Exciting Therapies Ahead in Prostate Cancer". P & T. 40 (8): 530–1. PMC . PMID 26236143.
- Kolvenbag GJ, Iversen P, Newling DW (2001). "Antiandrogen monotherapy: a new form of treatment for patients with prostate cancer". Urology. 58 (2 Suppl 1): 16–23. doi:10.1016/s0090-4295(01)01237-7. PMID 11502439.
- Carswell CI, Figgitt DP (2002). "Bicalutamide: in early-stage prostate cancer". Drugs. 62 (17): 2471–79; discussion 2480–1. doi:10.2165/00003495-200262170-00006. PMID 12421104.
- Jasmin C, Capanna R, Coia L, Coleman R, Saillant G (27 September 2005). Textbook of Bone Metastases. John Wiley & Sons. pp. 493–. ISBN 978-0-470-01160-7.
- Usami M, Akaza H, Arai Y, Hirano Y, Kagawa S, Kanetake H, Naito S, Sumiyoshi Y, Takimoto Y, Terai A, Yoshida H, Ohashi Y (2007). "Bicalutamide 80 mg combined with a luteinizing hormone-releasing hormone agonist (LHRH-A) versus LHRH-A monotherapy in advanced prostate cancer: findings from a phase III randomized, double-blind, multicenter trial in Japanese patients". Prostate Cancer Prostatic Dis. 10 (2): 194–201. doi:10.1038/sj.pcan.4500934. PMID 17199134.
In most countries, bicalutamide is given at a dose of 50 mg when used in combination with an LHRH-A. However, based on pharmacokinetic and pharmacodynamic data, the approved dose of bicalutamide in Japanese men is 80 mg per day.
- Shahani R, Fleshner NE, Zlotta AR (2007). "Pharmacotherapy for prostate cancer: the role of hormonal treatment". Discovery Medicine. 7 (39): 118–24. PMID 18093474.
- Bowsher W, Carter A (15 April 2008). Challenges in Prostate Cancer. John Wiley & Sons. pp. 146–. ISBN 978-1-4051-7177-9.
- United Nations (2005). Consolidated List of Products Whose Consumption And/or Sale Have Been Banned, Withdrawn, Severely Restricted Or Not Approved by Governments: Pharmaceuticals. United Nations Publications. pp. 4–. ISBN 978-92-1-130241-7.
- Bono AV (2004). "Overview of Current Treatment Strategies in Prostate Cancer". European Urology Supplements. 3 (1): 2–7. doi:10.1016/j.eursup.2003.12.002.
The Canadian Health Authorities have withdrawn the approval for antiandrogen monotherapy with bicalutamide for the treatment of localised prostate cancer . Several European countries have also withdrawn approval for bicalutamide for this indication.
- Nargund VH, Raghavan D, Sandler HM (17 January 2015). Urological Oncology. Springer. pp. 823–. ISBN 978-0-85729-482-1.
On the other hand, the 150 mg dose of bicalutamide has been associated with some safety concerns, such as a higher death rate when added to active surveillance in the early prostate cancer trialists group study , which has led the United States and Canada to recommend against prescribing the 150 mg dose .
- Moul JW (August 2009). "Twenty years of controversy surrounding combined androgen blockade for advanced prostate cancer". Cancer. 115 (15): 3376–8. doi:10.1002/cncr.24393. PMID 19484788.
- Kampel LJ (20 March 2012). Dx/Rx: Prostate Cancer. Jones & Bartlett Publishers. pp. 178–. ISBN 978-0-7637-9453-8.
- Tobias JS, Hochhauser D (3 October 2014). Cancer and its Management. Wiley. pp. 379–. ISBN 978-1-118-46871-5.
- Neal DE (1994). Tumours in Urology. Springer Science & Business Media. pp. 233–. ISBN 978-1-4471-2086-5. Archived from the original on 27 April 2016.
- Regitz-Zagrosek V (2 October 2012). Sex and Gender Differences in Pharmacology. Springer Science & Business Media. pp. 575–. ISBN 978-3-642-30725-6. Archived from the original on 24 June 2016.
- Kolinsky M, de Bono JS (2016). "The Ongoing Challenges of Targeting the Androgen Receptor". European Urology. 69 (5): 841–3. doi:10.1016/j.eururo.2015.10.052. PMID 26585581.
- "Bicalutamide". Kyoto Encyclopedia of Genes and Genomes (KEGG). Archived from the original on 26 November 2016.
- Morton I, Hal JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 51–. ISBN 978-94-011-4439-1. Archived from the original on 14 May 2016.
- Ganellin C, Triggle DJ (21 November 1996). Dictionary of Pharmacological Agents. CRC Press. pp. 570–. ISBN 978-0-412-46630-4. Archived from the original on 7 May 2016.
- Ferraro MB, Orendt AM, Facelli JC (19 September 2009). "Parallel Genetic Algorithms for Crystal Structure Prediction: Successes and Failures in Predicting Bicalutamide Polymorphs". In Huang D, Jo K, Lee H, Kang H, Bevilacqua V. Emerging Intelligent Computing Technology and Applications: 5th International Conference on Intelligent Computing, ICIC 2009 Ulsan, South Korea, September 16–19, 2009 Proceedings. Springer. pp. 120–. doi:10.1007/978-3-642-04070-2_14. ISBN 978-3-642-04070-2.
- Dhas NL, Ige PP, Kudarha RR (2015). "Design, optimization and in-vitro study of folic acid conjugated-chitosan functionalized PLGA nanoparticle for delivery of bicalutamide in prostate cancer". Powder Technology. 283: 234–245. doi:10.1016/j.powtec.2015.04.053.
- Yagiela JA, Dowd FJ, Johnson B, Mariotti A, Neidle EA (19 March 2010). Pharmacology and Therapeutics for Dentistry. Elsevier Health Sciences. pp. 851–. ISBN 0-323-07824-9.
- Hepler CD, Segal R (25 February 2003). Preventing Medication Errors and Improving Drug Therapy Outcomes: A Management Systems Approach. CRC Press. pp. 136–137. ISBN 978-0-203-01073-0.
- Dukes G, Dukes MN, Mildred M, Swartz B (January 1998). Responsibility for Drug-induced Injury: A Reference Book for Lawyers, the Health Professions and Manufacturers. IOS Press. pp. 241–8. ISBN 978-90-5199-387-5.
- "Bicalutamide Prices, Coupons and Patient Assistance Programs". Drugs.com. Archived from the original on 6 September 2015. Retrieved 31 August 2015.
- "Casodex Prices, Coupons and Patient Assistance Programs". Drugs.com. Archived from the original on 17 April 2016.
- Ramadan WH, Kabbara WK, Al Basiouni Al Masri HS (2015). "Enzalutamide for patients with metastatic castration-resistant prostate cancer". OncoTargets and Therapy. 8: 871–6. doi:10.2147/OTT.S80488. PMC . PMID 25945058.
- Stuhan MA (2 April 2013). Understanding Pharmacology for Pharmacy Technicians. ASHP. pp. 268–. ISBN 978-1-58528-360-6.
- Allan GF, Sui Z (2003). "Therapeutic androgen receptor ligands". Nucl Recept Signal. 1: e009. doi:10.1621/nrs.01009. PMC . PMID 16604181.
- Emans SJ, Laufer MR (5 January 2012). Emans, Laufer, Goldstein's Pediatric and Adolescent Gynecology. Lippincott Williams & Wilkins. pp. 365–. ISBN 978-1-4511-5406-1. Archived from the original on 16 May 2016.
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.
- Hillard PJ (29 March 2013). Practical Pediatric and Adolescent Gynecology. John Wiley & Sons. pp. 182–. ISBN 978-1-118-53857-9.
Treatment is expensive, with costs typicall in the range of $10,000–$15,000 per year.
- "Actavis Generic Prostate Cancer Drug Bicalutamide First to Market in UK, Germany, France". Press Release. AstraZeneca, Actavis. 10 July 2008.
- "Hormonal Therapies" (PDF). Future Oncology. 2 (2–3): 306. June 1996.
- "Zeneca of Britain Posts Strong Drug Profits". The New York Times. 12 March 1997.
- "Annual Report and Form 20-F 2001" (PDF). AstraZeneca.
- "Annual Report and Form 20-F 2004" (PDF). AstraZeneca.
- "Annual Report and Form 20-F 2007" (PDF). AstraZeneca.
- "Annual Report and Form 20-F 2010" (PDF). AstraZeneca.
- "Annual Report and Form 20-F 2013" (PDF). AstraZeneca.
- "Annual Report and Form 20-F 2016" (PDF). AstraZeneca. Archived (PDF) from the original on 3 April 2017.
- Chow H, Ghosh PM, deVere White R, Evans CP, Dall'Era MA, Yap SA, Li Y, Beckett LA, Lara PN, Pan CX (2016). "A phase 2 clinical trial of everolimus plus bicalutamide for castration-resistant prostate cancer". Cancer. 122 (12): 1897–904. doi:10.1002/cncr.29927. PMID 27019001. Lay summary – Cancer Network.
- Wang LG, Mencher SK, McCarron JP, Ferrari AC (2004). "The biological basis for the use of an anti-androgen and a 5-alpha-reductase inhibitor in the treatment of recurrent prostate cancer: Case report and review". Oncology Reports. 11 (6): 1325–9. PMID 15138573.
- Tay MH, Kaufman DS, Regan MM, Leibowitz SB, George DJ, Febbo PG, Manola J, Smith MR, Kaplan ID, Kantoff PW, Oh WK (2004). "Finasteride and bicalutamide as primary hormonal therapy in patients with advanced adenocarcinoma of the prostate". Annals of Oncology. 15 (6): 974–8. doi:10.1093/annonc/mdh221. PMID 15151957.
- Merrick GS, Butler WM, Wallner KE, Galbreath RW, Allen ZA, Kurko B (2006). "Efficacy of neoadjuvant bicalutamide and dutasteride as a cytoreductive regimen before prostate brachytherapy". Urology. 68 (1): 116–20. doi:10.1016/j.urology.2006.01.061. PMID 16844453.
- Sartor O, Gomella LG, Gagnier P, Melich K, Dann R (2009). "Dutasteride and bicalutamide in patients with hormone-refractory prostate cancer: the Therapy Assessed by Rising PSA (TARP) study rationale and design". The Canadian Journal of Urology. 16 (5): 4806–12. PMID 19796455.
- Chu FM, Sartor O, Gomella L, Rudo T, Somerville MC, Hereghty B, Manyak MJ (2015). "A randomised, double-blind study comparing the addition of bicalutamide with or without dutasteride to GnRH analogue therapy in men with non-metastatic castrate-resistant prostate cancer". European Journal of Cancer. 51 (12): 1555–69. doi:10.1016/j.ejca.2015.04.028. PMID 26048455.
- Gaudet M, Vigneault É, Foster W, Meyer F, Martin AG (2016). "Randomized non-inferiority trial of Bicalutamide and Dutasteride versus LHRH agonists for prostate volume reduction prior to I-125 permanent implant brachytherapy for prostate cancer". Radiotherapy and Oncology : Journal of the European Society for Therapeutic Radiology and Oncology. 118 (1): 141–7. doi:10.1016/j.radonc.2015.11.022. PMID 26702991.
- Dijkstra S, Witjes WP, Roos EP, Vijverberg PL, Geboers AD, Bruins JL, Smits GA, Vergunst H, Mulders PF (2016). "The AVOCAT study: Bicalutamide monotherapy versus combined bicalutamide plus dutasteride therapy for patients with locally advanced or metastatic carcinoma of the prostate-a long-term follow-up comparison and quality of life analysis". SpringerPlus. 5: 653. doi:10.1186/s40064-016-2280-8. PMC . PMID 27330919.
- Becker KL (2001). Principles and Practice of Endocrinology and Metabolism. Lippincott Williams & Wilkins. p. 1209. ISBN 978-0-7817-1750-2. Archived from the original on 28 June 2014.
- Lepor H (1993). "Medical therapy for benign prostatic hyperplasia". Urology. 42 (5): 483–501. doi:10.1016/0090-4295(93)90258-c. PMID 7694413.
The clinically significant adverse events reported in the casodex group included breast tenderness (93%), breast enlargement (54%), and sexual dysfunction (60%). In none of the patients in the placebo group did any of these adverse events develop. None of the subjects discontinued therapy owing to an adverse event.
- Lee M, Sharifi R (1997). "Benign prostatic hyperplasia: diagnosis and treatment guideline". Ann Pharmacother. 31 (4): 481–6. doi:10.1177/106002809703100415. PMID 9101011.
- Kenny B, Ballard S, Blagg J, Fox D (1997). "Pharmacological options in the treatment of benign prostatic hyperplasia". J. Med. Chem. 40 (9): 1293–315. doi:10.1021/jm960697s. PMID 9135028.
- Translational Breast Cancer Research Consortium (TBCRC) (2012). "Targeting the androgen receptor (AR) in women with AR+ ER-/PR- metastatic breast cancer (MBC)". J Clin Oncol (suppl): abstract 1006. Archived from the original on 10 July 2015.
- Clinical trial number NCT00468715 for "Bicalutamide in Treating Patients With Metastatic Breast Cancer" at ClinicalTrials.gov
- Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, Blackwell K, Rugo H, Nabell L, Forero A, Stearns V, Doane AS, Danso M, Moynahan ME, Momen LF, Gonzalez JM, Akhtar A, Giri DD, Patil S, Feigin KN, Hudis CA, Traina TA (October 2013). "Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic Breast Cancer". Clinical Cancer Research. 19 (19): 5505–12. doi:10.1158/1078-0432.CCR-12-3327. PMC . PMID 23965901.
- Caiazza F, Murray A, Madden SF, Synnott NC, Ryan EJ, O'Donovan N, Crown J, Duffy MJ (April 2016). "Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells". Endocrine-Related Cancer. 23 (4): 323–34. doi:10.1530/ERC-16-0068. PMID 26932782.
- Traina TA, et al. (2015). "Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC)". Journal of Clinical Oncology. 33 (suppl): abstr 1003. Archived from the original on 30 May 2016.
- Levine D, Park K, Juretzka M, Esch J, Hensley M, Aghajanian C, Lewin S, Konner J, Derosa F, Spriggs D, Iasonos A, Sabbatini P (December 2007). "A phase II evaluation of goserelin and bicalutamide in patients with ovarian cancer in second or higher complete clinical disease remission". Cancer. 110 (11): 2448–56. doi:10.1002/cncr.23072. PMID 17918264.
- Bonagura JD, Twedt DC (1 December 2013). Kirk's Current Veterinary Therapy XV. Elsevier Health Sciences. p. 908. ISBN 978-0-323-22762-9.
- Mitchell MA, Tully TN (2009). Manual of Exotic Pet Practice. Elsevier Health Sciences. p. 363. ISBN 1-4160-0119-0.
- Pilny AA (9 February 2014). Endocrinology, An Issue of Veterinary Clinics: Exotic Animal Practice. Elsevier Health Sciences. pp. 16–17. ISBN 978-0-323-26419-8.
In ferrets, 5 mg/kg [of bicalutamide] orally every 24 hours has been used clinically, but no controlled toxicologic or pharmacologic studies have been published at this time.
- Fox JG, Marini RP (26 March 2014). Biology and Diseases of the Ferret. Wiley. p. 980. ISBN 978-1-118-78273-6.
Other agents have been proposed for medical management of [adrenal-associated endocrinopathy] but have not been studied. Possibly medications include the androgen receptor blockers flutamide and bicalutamide, the anti-androgen finasteride, estrogen-inhibiting anastrozole, and another GnRH analog, goserelin. [...] None of these drugs have been tested in controlled clinical trials in ferrets.
- Tucker H, Crook JW, Chesterson GJ (1988). "Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides". J. Med. Chem. 31 (5): 954–9. doi:10.1021/jm00400a011. PMID 3361581.
- Furr BJ (June 1995). "Casodex: preclinical studies and controversies". Annals of the New York Academy of Sciences. 761 (1): 79–96. doi:10.1111/j.1749-6632.1995.tb31371.x. PMID 7625752.
- Furr BJ, Tucker H (January 1996). "The preclinical development of bicalutamide: pharmacodynamics and mechanism of action". Urology. 47 (1A Suppl): 13–25; discussion 29–32. doi:10.1016/S0090-4295(96)80003-3. PMID 8560673.
- Blackledge GR (1996). "Clinical progress with a new antiandrogen, Casodex (bicalutamide)". European Urology. 29 Suppl 2: 96–104. PMID 8717470.
- Kolvenbag GJ, Blackledge GR (January 1996). "Worldwide activity and safety of bicalutamide: a summary review". Urology. 47 (1A Suppl): 70–9; discussion 80–4. doi:10.1016/s0090-4295(96)80012-4. PMID 8560681.
- 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.
- Schellhammer PF, Davis JW (March 2004). "An evaluation of bicalutamide in the treatment of prostate cancer". Clinical Prostate Cancer. 2 (4): 213–9. doi:10.3816/CGC.2004.n.002. PMID 15072604.
- Cockshott ID (2004). "Bicalutamide: clinical pharmacokinetics and metabolism". Clinical Pharmacokinetics. 43 (13): 855–78. doi:10.2165/00003088-200443130-00003. PMID 15509184.
- 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.