Bicalutamide
(INN, USAN, BAN, JAN)
|
|
| Systematic (IUPAC) name |
|
N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide
|
| Clinical data |
| Trade names |
Casodex, Cosudex, Calutide, Kalumid |
| Drugs.com |
monograph |
| MedlinePlus |
a697047 |
Pregnancy
category |
|
Routes of
administration |
Oral |
| Legal status |
| Legal status |
|
| Pharmacokinetic data |
| Bioavailability |
Well-absorbed |
| Protein binding |
96% |
| Metabolism |
Hepatic (CYP3A4) |
| Biological half-life |
6 days (acute),[1]
7–10 days (chronic)[2] |
| Identifiers |
| CAS Number |
90357-06-5 Y |
| ATC code |
L02BB03 (WHO) |
| PubChem |
CID 2375 |
| IUPHAR/BPS |
2863 |
| DrugBank |
DB01128 Y |
| ChemSpider |
2284 Y |
| UNII |
A0Z3NAU9DP Y |
| KEGG |
D00961 N |
| ChEMBL |
CHEMBL63560 N |
| Synonyms |
ICI-176334[3] |
| PDB ligand ID |
198 (PDBe, RCSB PDB) |
| Chemical data |
| Formula |
C18H14F4N2O4S |
| Molar mass |
430.373 g/mol |
SMILES
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O=C(Nc1cc(c(C#N)cc1)C(F)(F)F)C(O)(C)CS(=O)(=O)c2ccc(F)cc2
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InChI
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InChI=1S/C18H14F4N2O4S/c1-17(26,10-29(27,28)14-6-3-12(19)4-7-14)16(25)24-13-5-2-11(9-23)15(8-13)18(20,21)22/h2-8,26H,10H2,1H3,(H,24,25) Y
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Key:LKJPYSCBVHEWIU-UHFFFAOYSA-N Y
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| NY (what is this?) (verify) |
Bicalutamide (brand name Casodex) is a synthetic, non-steroidal, pure antiandrogen that is used primarily in the treatment of prostate cancer.[3][4][5][6][7] It is also used in the treatment of hirsutism[8][9] and other androgen-dependent conditions and as a component of hormone replacement therapy for transgender women.[10][11] Bicalutamide acts as a selective antagonist of the androgen receptor (AR), preventing androgens like testosterone and dihydrotestosterone from binding to and activating the AR and hence exerting their biological effects. Developed and marketed by AstraZeneca,[12] the drug was approved in 1995 as a combination treatment (with a gonadotropin-releasing hormone (GnRH) analogue (e.g., leuprorelin) or surgical castration)[13][14] for stage D2 metastatic prostate cancer. Since then, it has also been approved and used, for instance in Germany, as a monotherapy for the treatment of an earlier stage of the disease, stage C or D1 locally advanced prostate cancer.[15][16]
Prior to the 2012 approval of enzalutamide, a recently introduced, stronger non-steroidal antiandrogen with superior effectiveness, bicalutamide was the most widely used antiandrogen in the treatment of prostate cancer, and was regarded as the standard-of-care antiandrogen for the treatment of the condition.[17][18]
It is on the WHO Model List of Essential Medicines, the most important medications needed in a basic health system.[19]
Contents
- 1 Medical uses
- 1.1 Prostate cancer
- 1.2 Other uses
- 1.2.1 Excess hair and acne
- 1.2.2 Hormone replacement therapy
- 1.2.3 Male early puberty
- 2 Side effects
- 2.1 Combination with a GnRH analogue
- 2.2 Gynecomastia
- 2.3 Rare reactions
- 3 Contraindications
- 3.1 Pregnancy
- 3.2 Hepatic impairment
- 4 Comparison with other antiandrogens
- 4.1 Flutamide and nilutamide
- 4.2 Enzalutamide
- 4.3 Cyproterone acetate and spironolactone
- 4.4 GnRH analogues
- 5 Pharmacology
- 5.1 Antiandrogen
- 5.1.1 Blood-brain-barrier permeability
- 5.1.2 Influences on hormone levels
- 5.1.3 Differences from GnRH analogues
- 5.1.4 Spermatogenesis and fertility
- 5.1.5 AR activation in prostate cancer
- 5.2 Other actions
- 5.2.1 Cytochrome P450 inhibitor
- 5.2.2 P-Glycoprotein inhibitor
- 5.2.3 GABAA receptor negative modulator
- 6 Pharmacokinetics
- 7 Research
- 7.1 Prostate cancer
- 7.2 Breast cancer
- 7.3 Ovarian cancer
- 8 See also
- 9 References
- 10 Further reading
- 11 External links
Medical uses
Prostate cancer
Bicalutamide is indicated as a means of androgen deprivation therapy for the treatment of stage D2 metastatic prostate cancer in combination with castration (pharmacological with a GnRH analogue or surgical with an orchiectomy)[20] or at a higher dosage as a monotherapy.[16][21] It has not been found to be effective as a monotherapy in prostate cancer at the same dosage as that in which it is approved in combination with a GnRH analogue.[22]
While efficacious initially, most advanced prostate cancer patients eventually become resistant to antiandrogen including bicalutamide therapy due to progressive mutations in the AR, resulting in the transformation of these drugs from antagonists into agonists of the AR.[23]
Other uses
Excess hair and acne
Low-dose bicalutamide has been found to be effective in the treatment of hirsutism in women.[8][9][24] The drug was well-tolerated, all of the patients experienced a visible decrease in hair density, and a highly significant clinical improvement was observed with the Ferriman–Gallwey score decreasing by 41.2% at three months and by 61.6% at six months.[25][26] Bicalutamide can also be used in the treatment of acne in women.[27][28] Several studies have demonstrated complete clearing of acne with flutamide in women, and similar benefits would be expected with bicalutamide.[29]
Hormone replacement therapy
Bicalutamide, along with other non-steroidal antiandrogens including flutamide and nilutamide, is used as a component of hormone replacement therapy for transgender women.[10][11][30] However, relative to flutamide and nilutamide, bicalutamide is preferred due to its superior safety and tolerability profiles and its longer half-life.[31][32]
Male early puberty
Bicalutamide is useful in combination with the aromatase inhibitor anastrozole as a puberty blocker in the treatment of male precocious puberty.[33][34] This is a cost-effective alternative to GnRH analogues for the treatment of this condition. Moreover, the combination is effective in gonadotropin-independent precocious puberty, namely familial male-limited precocious puberty (also known as testotoxicosis), where GnRH analogues notably are not effective.[33][34]
Side effects
The side effect profile of bicalutamide is highly sex-dependent. In women, the side effects of pure antiandrogens like bicalutamide are minimal and the drug is well-tolerated.[26] In men however, due to androgen deprivation, a variety of side effects of varying severity may occur during bicalutamide treatment, with breast pain/tenderness and gynecomastia being the most common[35] and others including physical feminization and demasculinization in general (e.g., decreased muscle mass and strength, a gynoid fat distribution, and decreased body hair growth),[35][36] hot flashes, fatigue, weakness, depression, sexual dysfunction (including loss of libido and erectile dysfunction),[37] and decreased bone density and an increased risk of fractures.[35] In addition, reduction of the weight of the prostate gland and seminal vesicles[38] (though not of the testes)[39] and, consequently, reversible hypospermia or aspermia (reduced or absent semen/ejaculate production) may occur.[40][41] However, in contrast, bicalutamide does not appear to adversely affect spermatogenesis, and thus may not necessarily abolish the capacity/potential for fertility.[39] General side effects of bicalutamide that may occur in either sex include diarrhea, nausea, dry skin,[42] and itching.[43][44][45][46]
Combination with a GnRH analogue
Coadministration of bicalutamide with a GnRH analogue modifies the side effect profile of the drug. Some of its side effects, including breast pain/tenderness and gynecomastia, are far less likely to occur when the drug is combined with a GnRH analogue,[47] while certain other side effects, including hot flashes, depression, fatigue, and sexual dysfunction,[48] occur much more frequently in combination with a GnRH analogue.[49][50][51] It is thought that this is due to the suppression of estrogen levels (in addition to androgen levels) by GnRH analogues, as estrogen may compensate for various negative central effects of androgen deprivation.[49] If bicalutamide is combined with a GnRH analogue or surgical castration, the elevation of androgen and estrogen levels in men caused by bicalutamide will be prevented and the side effects of excessive estrogens, namely gynecomastia, will be reduced.[47] However, due to the loss of estrogen, bone loss will accelerate and the risk of osteoporosis developing with long-term therapy will increase.[52]
Gynecomastia
In the case that bicalutamide is used as a monotherapy (and thus is not combined with a GnRH analogue), tamoxifen, a selective estrogen receptor modulator with antiestrogenic actions in breast tissue and estrogenic actions in bone, has been found to be effective in preventing and reversing bicalutamide-induced gynecomastia in men.[53][54] Moreover, in contrast to GnRH analogues, tamoxifen poses minimal risk of accelerated bone loss and osteoporosis.[53][54] For reasons that are unclear, anastrozole, an aromatase inhibitor (inhibitor of estrogen biosynthesis), has been found to be much less effective in comparison to tamoxifen for treating bicalutamide-induced gynecomastia.[53][54] A systematic review of non-steroidal antiandrogen-induced gynecomastia and breast tenderness concluded that tamoxifen (10–20 mg/day) and radiotherapy could effectively manage the side effect without relevant adverse effects, though with tamoxifen showing superior effectiveness.[55]
Rare reactions
Bicalutamide may rarely cause hepatic changes, such as transiently elevated levels of transaminases and jaundice.[56] In a study of 4,052 prostate cancer patients who received 150 mg/day bicalutamide as a monotherapy, the incidence of abnormal liver function tests was regarded as low at 3.4% for bicalutamide relative to 1.9% for standard care.[57] As such, though the risk is considered to be small, it is recommended that liver function be monitored during bicalutamide treatment.[35]
From a theoretical standpoint, flutamide, bicalutamide, and nilutamide are all thought to be capable of causing hepatotoxicity,[58][59] However, relative to flutamide (which has an estimated incidence rate of 3 in every 10,000), hepatotoxicity is much rarer with bicalutamide and nilutamide, and the risk is thought to be significantly less with nilutamide and even further less with bicalutamide.[2][59][60] A total of five cases of bicalutamide-associated hepatotoxicity have been reported in the medical literature,[56][61] out of millions of patient exposures.[1]
Several cases of interstitial pneumonitis in association with bicalutamide treatment have been reported in the medical literature.[62][63][64] The risk is considered to be very low and far less relative to that seen with nilutamide (which has a rather high estimated incidence rate of 1–2% of patients).[65][63][31]:81 A single case report of eosinophilic lung disease associated with bicalutamide treatment exists.[66][45]
There is a case report of bicalutamide-induced gynecomastia proceeding to breast cancer in a male prostate cancer patient.[67]
Contraindications
Pregnancy
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.[68][69][70][71] As such, bicalutamide is a teratogen, and may have the potential to produce undervirilization/sexually ambiguous genitalia in male fetuses.[68][69] For this reason, bicalutamide is contraindicated in women during pregnancy, and women who are sexually active and who can or may become pregnant must take bicalutamide only in combination with contraception.[68][69]
Hepatic impairment
In individuals with severe, though not mild-to-moderate hepatic impairment, there is evidence that the elimination of bicalutamide is slowed, and hence, caution should be observed in these patients.[72][73] The half-life of bicalutamide is unchanged in renal impairment.[74]
Comparison with other antiandrogens
Flutamide and nilutamide
Relative to the non-steroidal antiandrogens flutamide and nilutamide, bicalutamide has the highest affinity for the AR,[37][75] as well as the longest half-life (~6 days for bicalutamide versus 5–6 hours for flutamide and ~2 days for nilutamide).[31] It has 4-fold greater affinity for the AR than does 2-hydroxyflutamide, the active metabolite of flutamide (a prodrug),[76] and shows 5- to 10-fold the antiandrogenic potency of flutamide in vivo in rats.[77] The greater AR affinity and longer half-life of bicalutamide allow it to be used at relatively low dosages in comparison to flutamide and nilutamide.[78] Bicalutamide is regarded as the most potent of the three drugs as well as the safest and most well-tolerated.[1] It is for these reasons that it has largely replaced flutamide and nilutamide in clinical use.[58]
In accordance with the above, the efficacy of bicalutamide has been found to be at least equivalent to flutamide in the treatment of prostate cancer in a direct head-to-head comparison, and indications of superior efficacy, including significantly greater relative decreases and increases in levels of prostate-specific antigen and testosterone, respectively, were observed.[79][80]
Enzalutamide
In comparison to bicaclutamide, the newer non-steroidal antiandrogen enzalutamide has 5- to 8-fold higher affinity for the AR,[81][82] possesses mechanistic differences resulting in improved AR deactivation,[81][83] shows increased (though by no means complete) resistance to AR mutations in prostate cancer cells causing a switch from antagonist to agonist activity,[81][84] and has a longer half-life (8–9 days versus ~6 days for bicalutamide).[85] As such, enzalutamide appears to be a much more potent antiandrogen relative to bicalutamide. In accordance, it produces substantially greater compensatory increases in testosterone levels compared to bicalutamide at similar dosages (114% for enzalutamide 160 mg/day relative to 66% for bicalutamide 150 mg/day), and similar increases (with the 160 mg/day dosage) in testosterone, estradiol, and luteinizing hormone (LH) levels relative to high-dosage bicalutamide (300–600 mg/day).[86][87] Moreover, the drug has demonstrated superior clinical effectiveness in comparison to bicalutamide in the treatment of prostate cancer.[22] In terms of tolerability, enzalutamide and bicalutamide appear comparable in most regards, with a similar moderate negative effect on sexual function and activity for instance.[87] However, enzalutamide has a risk of seizures and other central side effects such as anxiety and insomnia related to off-target GABAA receptor inhibition that bicalutamide does not appear to have.[88][85][2] In addition, unlike bicalutamide, enzalutamide is still on-patent, and for this reason, is extremely expensive ($7,450 USD for a 30-day supply as of 2015).[89] Contrarily, the cost of bicalutamide is very low in comparison (from $15.44 for a 30-day supply of once-daily 50 mg tablets).[90]
Cyproterone acetate and spironolactone
In clinical studies, flutamide has been found to be more effective than both cyproterone acetate and spironolactone in the treatment of androgen-dependent conditions such as acne and hirsutism in women.[91][92][93] Bicalutamide has similarly been tried and found to be highly effective in the treatment of hirsutism in women.[8][9][24] However, although it has not been compared head-to-head with other antiandrogens in any trials for such conditions, relative to flutamide, the effectiveness of bicalutamide as an antiandrogen is equivalent or greater in the treatment of prostate cancer, and hence, the same would also be expected in the treatment of other androgen-dependent conditions (and versus antiandrogens that flutamide has been compared to).[31][37]
A study comparing the efficacy of 50 mg/day bicalutamide versus 300 mg/day cyproterone acetate in preventing the prostate-specific antigen flare at the start of GnRH agonist (specially goserelin acetate) therapy in men with prostate cancer found that the two regimens were equivalently effective.[94]
GnRH analogues
Non-steroidal antiandrogens including bicalutamide, flutamide, nilutamide, and enzalutamide show a significantly lower risk of certain side effects, including hot flashes, depression, fatigue, loss of libido, and decreased sexual activity, relative to treatment with GnRH analogues, maximal androgen blockade (non-steroidal antiandrogen and GnRH analogue combination), cyproterone acetate, or surgical castration in prostate cancer.[7][49][95][96] For example, 60% of men reported complete loss of libido with bicalutamide relative to 85% for maximal androgen blockade and 69% reported complete loss of erectile function relative to 93% for maximal androgen blockade.[7] Another large study reported a rate of impotence of only 9.3% with bicalutamide relative to 6.5% for standard care (the controls), a rate of decreased libido of only 3.6% with bicalutamide relative to 1.2% for standard care, and a rate of 9.2% with bicalutamide for hot flashes relative to 5.4% for standard care.[97] One other study reported decreased libido, impotence, and hot flashes in only 3.8%, 16.9%, and 3.1% of bicalutamide-treated patients, respectively, relative to 1.3%, 7.1%, and 3.6% for placebo.[98] It has been proposed that due to the lower relative effect of non-steroidal antiandrogens on sexual interest and activity, with two-thirds of advanced or metastatic prostate cancer patients treated with them retaining sexual interest, these drugs may result in improved quality of life and thus be preferable for those who wish to retain sexual interest and function relative to other antiandrogen therapies in prostate cancer.[49]
Pharmacology
Antiandrogen
Bicalutamide acts as a highly selective competitive silent antagonist of the AR. Although the affinity of bicalutamide for the AR is approximately 50 times lower than that of dihydrotestosterone (DHT),[75] the main endogenous ligand of the receptor in the prostate gland, sufficient concentrations of bicalutamide efficiently prevent activation of the AR by androgens including testosterone and DHT and subsequent upregulation of the transcription of androgen-responsive genes.[38][99] The drug has also notably been found to accelerate the degradation of the AR.[100] 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.[101] The active R-isomer also has a much longer half-life than the S-isomer,[101] and serum levels of (R)-bicalutamide are about 100-fold greater than those of (S)-bicalutamide at steady state.[102] Owing to its selectivity, unlike steroidal antiandrogens such as cyproterone acetate and megestrol acetate,[103] bicalutamide lacks additional, off-target hormonal side effects (e.g., progestogenic, glucocorticoid, or antimineralocorticoid), and neither inhibits nor suppresses androgen production in the body (i.e., it does not act as an antigonadotropin) – instead, it exclusively mediates its antiandrogen effects by blocking androgen binding and subsequent receptor activation at the level of the AR.[78][101]
Blood-brain-barrier permeability
Based on animal research, it was initially thought that bicalutamide was unable to cross the blood-brain-barrier and hence was a peripherally-selective antiandrogen.[38][79] This conclusion was drawn from the finding that bicalutamide does not increase LH or testosterone levels in animals (including in rats and dogs),[38][79][104][105] as antiandrogens like flutamide normally do this by blocking ARs in the hypothalamus and pituitary gland and thereby disinhibiting the hypothalamic-pituitary-gonadal (HPG) axis.[49] In humans however, bicalutamide has been found to increase LH and testosterone levels, and to a comparative extent relative to flutamide and nilutamide.[49][72][79][106][107] As such, it appears that bicalutamide does indeed cross the blood-brain-barrier in humans and affect central function, as supported by potential side effects such as diminished sexual interest, fatigue, and depression in men.[48] It has been stated that this difference of bicalutamide in animals and humans may be due to species-related differences in drug tissue distribution.[72][107]
Influences on hormone levels
In men, blockade of the AR by bicalutamide in the hypothalamus and pituitary gland suppresses the negative feedback of androgens on the release of LH, resulting in an elevation in LH levels.[49] Follicle-stimulating hormone (FSH) levels, in contrast, remain essentially unchanged.[77] The increase in LH levels leads to a significant increase in androgen and estrogen levels, by up to two-fold in the case of the former.[108] Bicalutamide will more than block the effects of the increased androgen levels (monotherapy is still clinically effective in the treatment of prostate cancer, for instance),[15] but the effects of the elevated estrogen levels will remain unopposed, and are responsible for the feminizing side effects the drug in males, most notably gynecomastia.[109] It is noteworthy that bicalutamide increases androgen and estrogen levels only in men and not in women; this is because androgen levels are far lower in women in comparison and in turn exert little to no basal suppression of the HPG axis.[110][111][112] Dosages of bicalutamide of 10 mg, 30 mg, and 50 mg per day have been found to produce a moderate effect on sex hormone levels in men with prostate cancer, providing indication that the drug has clinically-relevant antiandrogen effects at a dosage as low as 10 mg/day.[113]
Differences from GnRH analogues
It has been proposed that the increase in estrogen levels caused by non-steroidal antiandrogens 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, maximal androgen blockade, and cyproterone acetate (which, in contrast, decrease both androgen and estrogen levels).[95][96][114] 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.[95][96][114]
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 3β-androstanediol is also a potent GABAA receptor-potentiating neurosteroid.[115][116] Due to the fact that bicalutamide does not lower androgen levels, the levels of these androgen metabolites are likely not lowered either, unlike with therapies such as GnRH analogues. (In fact, since bicalutamide actually increases testosterone levels in males, the levels of these metabolites might be elevated similarly.) These steroids have been found to have AR-independent positive effects on sexual motivation,[115][116][117][118] and may explain the preservation of sexual interest and function by bicalutamide and other non-steroidal antiandrogens. They also have antidepressant, anxiolytic, and cognitive-enhancing effects,[118][119][120][121] and may account for the lower incidence of depression with bicalutamide and other non-steroidal antiandrogens relative to other antiandrogen therapies.
Spermatogenesis and fertility
Unlike with antigonadotropic antiandrogens such as cyproterone acetate, spironolactone, 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).[39] This may be explained by the fact that testosterone levels are far higher in the testes than in the rest of the body (concentrations in the seminiferous tubules are 20- to 100-fold greater than circulating levels, for instance),[122] and on account of the extremely high levels of androgens that are present, it is likely that systemic bicalutamide therapy is unable to produce intratesticular concentrations of the drug that are able to significantly block androgen action in this part of the body.[39] This is especially so considering that bicalutamide increases circulating testosterone levels, and by extension gonadal testosterone production, by up to two-fold in males.[108] In addition, it is notable that only a fraction (5–10%) of normal intratesticular levels of testosterone (and hence androgen action) is actually necessary to maintain spermatogenesis in human males.[123][124]
In contrast to bicalutamide and other pure/non-steroidal antiandrogens, antigonadotropic antiandrogens suppress gonadotropin secretion, which in turn diminishes testosterone production by the testes as well as the maintenance of the testes by gonadotropins, resulting in atrophy and loss of their function.[125] As such, bicalutamide and other non-steroidal antiandrogens may uniquely have the potential to preserve testicular function and spermatogenesis and thus male fertility relative to alternative therapies.[39][126] In accordance with this notion, a study found that prolonged, high-dose bicalutamide treatment had minimal effects on fertility in male rats.[127] 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.[3]
AR activation in prostate cancer
Though a pure, or silent antagonist of the AR under normal circumstances, bicalutamide, as well as other earlier antiandrogens like flutamide and nilutamide, have been found to possess weak partial agonist properties in the setting of AR overexpression and agonist activity in the case of certain mutations in the ligand-binding domain of the AR.[128][129] 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.[128][130] This is the mechanism of the phenomenon of antiandrogen withdrawal syndrome, where antiandrogen discontinuation paradoxically slows the rate of tumor growth.[130] 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.[128]
Other actions
Cytochrome P450 inhibitor
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.[72] 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).[72] In animals, bicalutamide has been found to be an inducer of certain cytochrome P450 enzymes.[72] However, dosages of 150 mg/day or less have shown no evidence of this in humans.[72]
Bicalutamide has been identified as a strong CYP27A1 inhibitor in vitro.[131] CYP27A1 converts cholesterol into 27-hydroxycholesterol, an oxysterol that has multiple biological functions including direct, tissue-specific activation of the estrogen receptor (it has been characterized as a selective estrogen receptor) and the liver X receptor.[131] 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.[131]
P-Glycoprotein inhibitor
Bicalutamide, as well as enzalutamide, have been found to act as inhibitors of P-glycoprotein (ABCB1) efflux and ATPase activity.[132][133][134] This action may reverse docetaxel resistance in prostate cancer cells by reducing transport of the drug out of these cells.[132][133][134]
GABAA receptor negative modulator
All of the approved non-steroidal antiandrogens, flutamide, nilutamide, bicalutamide, and enzalutamide, have been found to possess an off-target action of inhibiting GABAA receptor currents in vitro to varying extents.[88] In addition, flutamide, nilutamide, and enzalutamide have been found to cause convulsions and/or death in mice at sufficient doses.[88] Bicalutamide was notably not found to do this, but this may have simply been due to the fact that the brain penetration of bicalutamide is limited in this species.[88] In any case, regardless of animal findings, enzalutamide is the only approved non-steroidal antiandrogen that has been found to be associated with a significantly increased incidence of seizures clinically, so the relevance of aforementioned findings with regard to bicalutamide and the other drugs is dubious.[88]
Pharmacokinetics
Bicalutamide has a very long serum half-life of about 6 days with a single dose,[1] and a half-life of 7–10 days with repeated administration, allowing for once-daily dosing.[2] Steady-state concentrations of the drug are reached after 12 weeks at a dosage of 50 mg/day, with an approximately 10-fold accumulation.[77][135] Bicalutamide is almost exclusively metabolized by the enzyme CYP3A4.[72][102] Oral dosages of bicalutamide of 300–600 mg per day result in similar plasma levels of the drug, indicating a saturation of absorption and resulting in similar degrees of efficacy, tolerability, and toxicity.[136]
Research
Prostate cancer
A phase II clinical trial of bicalutamide with everolimus in castration-resistant prostate cancer showed promising responses.[137]
Breast cancer
Bicalutamide has been tested with good results for the treatment of AR-positive ER/PR-negative locally advanced and metastatic breast cancer in a phase II study for this indication.[138][139][140] The newer non-steroidal antiandrogen enzalutamide may also hold some promise for this type of cancer.[141][4]
Ovarian cancer
Bicalutamide has been researched in clinical trials for ovarian cancer, with effectiveness observed.[142]
See also
- Discovery and development of antiandrogens
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- ^ a b P. Jorge Chedrese (13 June 2009). Reproductive Endocrinology: A Molecular Approach. Springer Science & Business Media. pp. 233–. ISBN 978-0-387-88186-7.
- ^ 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". Front Aging Neurosci 2: 15. doi:10.3389/fnagi.2010.00015. PMC 2874398. PMID 20552051.
- ^ Huang, Q; Zhu, H; Fischer, D; Zhou, J (2008). "An estrogenic effect of 5α-androstane-3β, 17β-diol on the behavioral response to stress and on CRH regulation". Neuropharmacology 54 (8): 1233–1238. doi:10.1016/j.neuropharm.2008.03.016. ISSN 0028-3908.
- ^ Frye, C; Koonce, C; Edinger, K; Osborne, D; Walf, A (2008). "Androgens with activity at estrogen receptor beta have anxiolytic and cognitive-enhancing effects in male rats and mice". Hormones and Behavior 54 (5): 726–734. doi:10.1016/j.yhbeh.2008.07.013. ISSN 0018-506X.
- ^ Wolf-Bernhard Schill; Frank H. Comhaire; Timothy B. Hargreave (26 August 2006). Andrology for the Clinician. Springer Science & Business Media. pp. 76–. ISBN 978-3-540-33713-3.
- ^ Eberhard Nieschlag; Hermann M. Behre; Susan Nieschlag (26 July 2012). Testosterone: Action, Deficiency, Substitution. Cambridge University Press. pp. 130–. ISBN 978-1-107-01290-5.
- ^ C.Y. Cheng (24 October 2009). Molecular Mechanisms in Spermatogenesis. Springer Science & Business Media. pp. 258–. ISBN 978-0-387-09597-4.
- ^ Leonard R. Johnson (14 October 2003). Essential Medical Physiology. Academic Press. pp. 731–. ISBN 978-0-08-047270-6.
- ^ John P. Mulhall (21 February 2013). Fertility Preservation in Male Cancer Patients. Cambridge University Press. pp. 84–. ISBN 978-1-139-61952-3.
- ^ Iswaran TJ, Imai M, Betton GR, Siddall RA (1997). "An overview of animal toxicology studies with bicalutamide (ICI 176,334)". J Toxicol Sci 22 (2): 75–88. PMID 9198005.
- ^ a b c Bambury RM, Scher HI (2015). "Enzalutamide: Development from bench to bedside". Urol. Oncol. 33 (6): 280–8. doi:10.1016/j.urolonc.2014.12.017. PMID 25797385.
- ^ Bambury, Richard M.; Rathkopf, Dana E. (2015). "Novel and next-generation androgen receptor–directed therapies for prostate cancer: Beyond abiraterone and enzalutamide". Urologic Oncology: Seminars and Original Investigations. doi:10.1016/j.urolonc.2015.05.025. ISSN 1078-1439.
- ^ a b Pinto Á (2014). "Beyond abiraterone: new hormonal therapies for metastatic castration-resistant prostate cancer". Cancer Biol. Ther. 15 (2): 149–55. doi:10.4161/cbt.26724. PMC 3928129. PMID 24100689.
- ^ a b c Mast N, Lin JB, Pikuleva IA (2015). "Marketed Drugs Can Inhibit Cytochrome P450 27A1, a Potential New Target for Breast Cancer Adjuvant Therapy". Mol. Pharmacol. 88 (3): 428–36. doi:10.1124/mol.115.099598. PMID 26082378.
- ^ a b Zhu Y, Liu C, Armstrong C, Lou W, Sandher A, Gao AC (May 2015). "Antiandrogens Inhibit ABCB1 Efflux and ATPase Activity and Reverse Docetaxel Resistance in Advanced Prostate Cancer". Clinical Cancer Research. doi:10.1158/1078-0432.CCR-15-0269. PMID 25995342.
- ^ a b Fenner A (Jul 2015). "Prostate cancer: Antiandrogens reverse docetaxel resistance via ABCB1 inhibition". Nature Reviews. Urology 12 (7): 361. doi:10.1038/nrurol.2015.135. PMID 26057062.
- ^ a b Armstrong CM, Gao AC (2015). "Drug resistance in castration resistant prostate cancer: resistance mechanisms and emerging treatment strategies". Am J Clin Exp Urol 3 (2): 64–76. PMC 4539108. PMID 26309896.
- ^ Denis, Louis; Mahler, C. (1996). "Pharmacodynamics and pharmacokinetics of bicalutamide: defining an active dosing regimen". Urology 47 (1): 26–28. doi:10.1016/S0090-4295(96)80004-5. ISSN 0090-4295.
- ^ Tyrrell CJ, Iversen P, Tammela T, Anderson J, Björk T, Kaisary AV, Morris T (Sep 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.
- ^ Bicalutamide/Everolimus Combo Promising in CRPC. April 2016
- ^ 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).
- ^ 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 (Oct 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 4086643. PMID 23965901.
- ^ Caiazza, Francesco; Murray, Alyson; Madden, Stephen F; Synnott, Naoise C; Ryan, Elizabeth J; O’Donovan, Norma; Crown, John; Duffy, Michael J (2016). "Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells". Endocrine-Related Cancer 23 (4): 323–334. doi:10.1530/ERC-16-0068. ISSN 1351-0088.
- ^ Levine D, Park K, Juretzka M, Esch J, Hensley M, Aghajanian C, Lewin S, Konner J, Derosa F, Spriggs D, Iasonos A, Sabbatini P (Dec 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.
Further reading
- Fradet, Yves (2014). "Bicalutamide (Casodex®) in the treatment of prostate cancer". Expert Review of Anticancer Therapy 4 (1): 37–48. doi:10.1586/14737140.4.1.37. ISSN 1473-7140.
- Schellhammer, Paul F.; Davis, John W. (2004). "An Evaluation of Bicalutamide in the Treatment of Prostate Cancer". Clinical Prostate Cancer 2 (4): 213–219. doi:10.3816/CGC.2004.n.002. ISSN 1540-0352.
- Wellington, Keri; Keam, Susan J (2006). "Bicalutamide 150 mg: a review of its use in the treatment of locally advanced prostate cancer". Drugs 66 (6): 837–850. doi:10.2165/00003495-200666060-00007. ISSN 0012-6667.
External links
- Casodex® (bicalutamide) Tablets - U.S. Food and Drug Administration
- Bicalutamide - AdisInsight
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Androgens and antiandrogens
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| Androgens |
| Agonists |
- Anabolic steroids (see here instead)
- Androgenic progestins (e.g., norethisterone, levonorgestrel, medroxyprogesterone acetate)
- Androstanolone
- Androstenediol
- Androstenedione
- DHEA
- DHEA sulfate
- Dihydrotestosterone
- Fluoxymesterone
- Mesterolone
- Methyltestosterone
- Testosterone#
- Testosterone acetate
- Testosterone capropate
- Testosterone cypionate
- Testosterone decanoate
- Testosterone enanthate
- Testosterone isocaproate
- Testosterone phenylpropionate
- Testosterone propionate
- Testosterone undecanoate
- Tibolone
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| SARMs |
- AC-262,356§
- Andarine§
- BMS-564,929§
- Enobosarm (ostarine)§
- LGD-2226§
- LGD-3303§
- S-23§
- S-40503§
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|
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| Antiandrogens |
| Antagonists |
- Abiraterone acetate
- Apalutamide†
- Bicalutamide
- Canrenoic acid
- Canrenone
- Chlormadinone acetate
- Cimetidine
- Cyproterone acetate
- Drospirenone
- Enzalutamide
- EPI-001§
- Flutamide
- Galeterone†
- Ketoconazole
- Megestrol acetate
- Nilutamide
- Nomegestrol acetate
- ODM-201†
- Osaterone acetate
- Oxendolone
- Potassium canrenoate
- Seviteronel†
- Spironolactone
- Topilutamide (fluridil)
- Valproic acid
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|
| Enzyme inhibitors |
| 5α-Reductase |
- Alfatradiol
- Chlormadinone acetate
- Dutasteride
- Finasteride
- Saw palmetto extract
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| CYP17A1 |
- Abiraterone acetate
- Cyproterone acetate
- Danazol
- Galeterone†
- Gestrinone
- Ketoconazole
- Orteronel†
- Seviteronel†
- Spironolactone
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| Others |
- Abiraterone acetate
- Aminoglutethimide
- Cyproterone acetate
- Danazol
- Gestrinone
- Ketoconazole
- Mitotane
- Trilostane
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|
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| Antigonadotropins |
- Anabolic steroids (e.g., nandrolone, oxandrolone)
- Estrogens (e.g., estradiol)
- GnRH agonists (e.g., leuprorelin)
- GnRH antagonists (e.g., cetrorelix)
- Progestogens (incl. allylestrenol, chlormadinone acetate, cyproterone acetate, delmadinone acetate, dydrogesterone, medroxyprogesterone acetate, megestrol acetate, nomegestrol acetate, norethisterone acetate, progesterone, spironolactone)
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-
- #WHO-EM
- ‡Withdrawn from market
- Clinical trials:
- †Phase III
- §Never to phase III
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Androgenics
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Receptor
(ligands) |
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AR
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Agonists
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Mixed (SARMs)
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- AC-262,356
- Andarine
- BMS-564,929
- Enobosarm (ostarine)
- LGD-2226
- LGD-3303
- LGD-4033
- RAD140
- S-23
- S-40503
- TFM-4AS-1
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Antagonists
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- 3α-Hydroxytibolone
- 3β-Hydroxytibolone
- Abiraterone
- Abiraterone acetate
- Apalutamide
- AZD-3514
- BAY-1024767
- Bisphenols (e.g., BADGE, BFDGE, bisphenol A, bisphenol F, bisphenol S)
- Benorterone
- Bicalutamide
- BMS-641,988
- BOMT
- Canrenoic acid
- Canrenone
- Chlormadinone acetate
- Cimetidine
- Cioteronel
- Clometerone
- Cyproterone
- Cyproterone acetate
- Delanterone
- DDT (via metabolite p,p’-DDE)
- Dieldrin
- Dienogest
- Drospirenone
- Endosulfan
- Enzalutamide
- EPI-001
- EPI-506
- Epitestosterone
- Fenarimol
- Flutamide
- Galeterone
- Guggulsterone
- Hydroxyflutamide
- Inocoterone
- Inocoterone acetate
- Ketoconazole
- Lavender oil
- Linuron
- Megestrol acetate
- Mespirenone
- Methiocarb
- Metogest
- Mifepristone
- Nilutamide
- Nomegestrol
- Nordinone
- ODM-201
- ONC1-13B
- ORM-15341
- Osaterone
- Osaterone acetate
- Oxendolone
- Pentomone
- PF-998425
- Potassium canrenoate
- Prochloraz
- Procymidone
- R-2956
- Rosterolone
- RU-58642
- RU-58841
- Seviteronel
- Spironolactone
- Spirorenone
- Topilutamide (fluridil)
- Topterone
- Valproic acid
- Vinclozolin
- Zanoterone
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| Enzyme |
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Modulators
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- See here instead (modulators of 20,22-desmolase, 17α-hydroxylase/17,20-lyase, 3β-HSD, 17β-HSD, 5α-reductase, and aromatase).
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| Others |
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Precursors/prohormones
|
- Cholesterol
- 22R-Hydroxycholesterol
- 20α,22R-Dihydroxycholesterol
- Pregnenolone
- Pregnenolone sulfate
- 17-Hydroxypregnenolone
- Progesterone
- 17-Hydroxyprogesterone
- 11-Deoxycortisol (cortodoxone)
- DHEA
- DHEA sulfate
- Δ5-Androstenediol
- Δ4-Androstenedione
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Indirect
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- Antigonadotropins (e.g., estrogens, progestogens, prolactin)
- GnRH agonists (e,g, GnRH, leuprorelin)
- GnRH antagonists (e.g., cetrorelix)
- Gonadotropins (e.g., FSH, hCG, LH)
- Kisspeptin
- Plasma proteins (ABP, albumin, SHBG)
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See also: Estrogenics • Glucocorticoids • Mineralocorticoids • Progestogenics
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Steroid hormone metabolism modulators
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| 20,22-Desmolase |
- Inhibitors: 22-ABC
- 3,3′-Dimethoxybenzidine
- 3-Methoxybenzidine
- Aminoglutethimide
- Canrenone
- Cyanoketone
- Danazol
- Etomidate
- Ketoconazole
- Mitotane
- Spironolactone
- Trilostane
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|
17α-Hydroxylase,
17,20-Lyase |
- Inhibitors: 22-ABC
- 22-Oxime
- Abiraterone
- Abiraterone acetate
- Amphenone
- Bifonazole
- Canrenone
- CFG-920
- Clotrimazole
- Cyanoketone
- Cyproterone acetate
- Danazol
- Econazole
- Galeterone
- Gestrinone
- Isoconazole
- Ketoconazole
- L-39
- Levoketoconazole
- Liarozole
- LY-207,320
- MDL-27,302
- Miconazole
- Mifepristone
- Orteronel
- Pioglitazone
- Prochloraz
- Rosiglitazone
- Seviteronel
- Spironolactone
- Stanozolol
- SU-9055
- SU-10603
- TGF-β
- Tioconazole
- Troglitazone
- VN/87-1
- YM116
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|
| 3α-HSD |
- Inhibitors: Coumestrol
- Daidzein
- Genistein
- Indomethacin
- Medroxyprogesterone acetate
- Inducers: Fluoxetine
- Fluvoxamine
- Mirtazapine
- Paroxetine
- Sertraline
- Venlafaxine
|
|
| 3β-HSD |
- Inhibitors: 4-MA
- Abiraterone
- Abiraterone acetate
- Azastene
- Cyanoketone
- Cyproterone acetate
- Danazol
- Epostane
- Genistein
- Gestrinone
- Metyrapone
- Norethisterone
- Oxymetholone
- Pioglitazone
- Rosiglitazone
- Trilostane
- Troglitazone
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|
| 11β-HSD |
- Inhibitors: 18α-Glycyrrhizic acid
- ABT-384
- Acetoxolone
- Carbenoxolone
- Enoxolone (glycyrrhetinic acid)
- Epigallocatechin gallate
- Glycyrrhizin (glycyrrhizic acid)
|
|
| 21-Hydroxylase |
- Inhibitors: Aminoglutethimide
- Amphenone B
- Bifonazole
- Canrenone
- Clotrimazole
- Diazepam
- Econazole
- Genistein
- Isoconazole
- Ketoconazole
- Levoketoconazole
- Metyrapone
- Miconazole
- Midazolam
- Spironolactone
- Tioconazole
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|
| 11β-Hydroxylase |
- Inhibitors: Abiraterone
- Abiraterone acetate
- Aminoglutethimide
- Canrenone
- Etomidate
- Fadrozole
- FETO
- Ketoconazole
- Levoketoconazole
- Metomidate
- Metyrapol
- Metyrapone
- Mitotane
- Potassium canrenoate
- Spironolactone
- Trilostane
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| 18-Hydroxylase |
- Inhibitors: 18-Ethynylprogesterone (18-ethinylprogesterone)
- 18-Vinylprogesterone
- Aminoglutethimide
- Canrenone
- FAD286
- Fadrozole
- Ketoconazole
- LCI699
- Metyrapone
- Mespirenone
- Potassium canrenoate
- Spironolactone
|
|
| 17β-HSD |
- Inhibitors: Danazol
- Simvastatin
|
|
| 5α-Reductase |
- Inhibitors: 22-Oxime
- Alfatradiol
- Azelaic acid
- β-Sitosterol
- Bexlosteride
- Chlormadinone acetate
- Cl-4AS-1
- Dutasteride
- Epitestosterone
- Epristeride
- Fatty acids (α-linolenic acid, linoleic acid, γ-linolenic acid, monolinolein, oleic acid)
- Finasteride
- Ganoderic acid
- Izonsteride
- L-39
- Lapisteride
- Oxendolone
- Saw palmetto
- TFM-4AS-1
- Turosteride
- Vitamin B6
- Zinc
|
|
| Aromatase |
- Inhibitors: 4-AT
- 4-Cyclohexylaniline
- 4-Hydroxytestosterone
- 5α-DHNET
- Abyssinone II
- Aminoglutethimide
- Anastrozole
- Ascorbic acid (vitamin C)
- Atamestane
- ATD
- Bifonazole
- CGP-45,688
- CGS-47,645
- Chalconoids (e.g., isoliquiritigenin)
- Corynesidone A
- Clotrimazole
- DHT
- Difeconazole
- Econazole
- Ellagitannins
- Endosulfan
- Exemestane
- Fadrozole
- Fatty acids (e.g., conjugated linoleic acid, linoleic acid, linolenic acid, palmitic acid)
- Fenarimol
- Finrozole
- Flavonoids (e.g., 7-hydroxyflavone, 7-hydroxyflavanone, 7,8-DHF, acacetin, apigenin, baicalein, biochanin A, chrysin, EGCG, gossypetin, hesperetin, liquiritigenin, myricetin, naringenin, pinocembrin, rotenone, quercetin, sakuranetin, tectochrysin)
- Formestane
- Imazalil
- Isoconazole
- Ketoconazole
- Letrozole
- Liarozole
- Melatonin
- MEN-11066
- Miconazole
- Minamestane
- Nimorazole
- NKS01
- Norendoxifen
- ORG-33,201
- Penconazole
- Phenytoin
- Prochloraz
- PGE2 (dinoprostone)
- Plomestane
- Prochloraz
- Propioconazole
- Pyridoglutethimide
- Quinolinoids (e.g., berberine, casimiroin, triptoquinone A, XHN22, XHN26, XHN27)
- Resorcylic acid lactones (e.g., zearalenone)
- Rogletimide
- Stilbenoids (e.g., resveratrol)
- Talarozole
- Terpenoids (e.g., dehydroabietic acid, (–)-dehydrololiolide, retinol (vitamin A), Δ9-THC, tretinoin)
- Testolactone
- Tioconazole
- Triadimefon
- Triadimenol
- Troglitazone
- Valproic acid
- Vorozole
- Xanthones (e.g., garcinone D, garcinone E, α-mangostin, γ-mangostin, monodictyochrome A, monodictyochrome B)
- YM-511
- Zinc
- Inducers: Atrazine
- Flavonoids (e.g., genistein, quercetin)
|
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| 27-Hydroxylase |
- Inhibitors: Anastrozole
- Bicalutamide
- Dexmedetomidine
- Fadrozole
- Posaconazole
- Ravuconazole
|
|
|
See also: Androgenics • Estrogenics • Glucocorticoidics • Mineralocorticoidics • Progestogenics
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