|Systematic (IUPAC) name|
|Biological half-life||6 days|
|CAS Registry Number|
|PDB ligand ID||198 (, )|
|Molecular mass||430.373 g/mol|
|(what is this?)|
Bicalutamide (INN, USAN, BAN) (brand names Casodex, Cosudex, Calutide, Kalumid) is a synthetic, non-steroidal, peripherally-selective, pure antiandrogen used in the treatment of prostate cancer, hirsutism, and other androgen-dependent conditions. Developed and marketed by AstraZeneca, bicalutamide was approved in 1995 as a combination treatment (with a gonadotropin-releasing hormone (GnRH) analogue (e.g., leuprorelin) or surgical castration) for advanced prostate cancer and has since also been used as a monotherapy for the treatment of earlier stages of the disease. Prior to the approval of enzalutamide, a recently introduced, newer non-steroidal antiandrogen with theoretically improved effectiveness, bicalutamide was regarded as the standard-of-care antiandrogen for the treatment of prostate cancer.
Bicalutamide is indicated for the treatment of stage D2 metastatic prostate cancer in combination with castration (pharmacological with a GnRH analogue or surgical with an orchiectomy) or as a monotherapy. However, while effective, most advanced prostate cancer patients eventually become resistant to antiandrogen including bicalutamide therapy.
Relative to the other non-steroidal antiandrogens flutamide and nilutamide, bicalutamide has the highest affinity for the androgen receptor (AR) (e.g., 4-fold greater than flutamide), as well as the longest half-life (~6 days for bicalutamide versus 5–6 hours for flutamide and ~2 days for nilutamide). Bicalutamide is described as the most potent of the non-steroidal antiandrogens as well as the most well-tolerated (not including/considering enzalutamide). It is for these reasons, as well as a better safety profile, that bicalutamide has largely replaced flutamide and nilutamide in the treatment of prostate cancer.
Bicalutamide, along with other non-steroidal antiandrogens including flutamide and nilutamide, is used as a component of hormone replacement therapy for trans women. However, relative to flutamide and nilutamide, bicalutamide is, in general, clinically preferred due to its superior safety, tolerability, and pharmacokinetic profiles.
In clinical studies, flutamide has been found to be more effective than both spironolactone and cyproterone acetate in the treatment of androgen-dependent conditions such as acne and hirsutism in women. Bicalutamide has similarly been tried and found to be effective in the treatment of hirsutism in women. However, although it has not been compared head-to-head with other antiandrogens in any trials, relative to flutamide, as mentioned above, bicalutamide is several times more potent and has a much longer half-life, and hence would be expected to be at least equivalent or perhaps even more effective in comparison.
It is noteworthy that monotherapy with non-steroidal, pure antiandrogens including flutamide and bicalutamide increases androgen and estrogen levels in men, but that this does not occur in women. As such, bicalutamide on its own may be relatively more effective as an antiandrogen in women. However, monotherapy with higher dosages of bicalutamide (150 mg/day) has still been found to be highly effective in the treatment of prostate cancer in men, and thus as an antiandrogen.
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 and has been used off-label for this indication. The newer non-steroidal antiandrogen enzalutamide may also hold some promise for this type of cancer but has been so far tested only in vitro. Bicalutamide has also been researched in clinical trials for ovarian cancer, with effectiveness seen.
Due to its actions as an antiandrogen, bicalutamide is a teratogen and should not be handled by women who are or who may become pregnant. It is known to have the potential to cause fetal defects, such as ambiguous genitalia.
Known potential side effects of bicalutamide, some of which may include breast pain/tenderness, gynecomastia, hot flashes, depression, fatigue, sexual dysfunction (including loss of libido and erectile dysfunction), diarrhea, nausea, pruritus (itching), and, rarely, hepatic changes (e.g., transiently elevated levels of transaminases, jaundice).
Some of the above-listed side effects, including breast pain/tenderness and gynecomastia, are far less likely to occur when bicalutamide is combined with a GnRH analogue (due to suppression of estrogen levels), and others, including hot flashes, depression, fatigue, and loss of libido, may occur only or may occur much more often when bicalutamide is combined with a GnRH analogue. In regards to the latter side effects, this is because bicalutamide is peripherally-selective and does not antagonize androgen action in the brain, and by itself, does not lower androgen levels. As such, brain androgen action remains normal or even increased with bicalutamide monotherapy (as bicalutamide by itself increases serum androgen levels).
From a theoretical standpoint, flutamide, nilutamide, and bicalutamide are all thought to be capable of causing hepatotoxicity, However, relative to flutamide (which has an estimated incidence rate of 3 in every 10,000, or 0.0003%), hepatotoxicity is much rarer in nilutamide and bicalutamide, and the risk is thought to be significantly less with nilutamide and even further less with bicalutamide. A total of four cases of bicalutamide-associated hepatotoxicity have been reported in the medical literature.
A few cases of interstitial pneumonitis in association with bicalutamide treatment have been reported in the medical literature. Incidence is very rare, and the risk of interstitial pneumonitis is far less relative to that seen with nilutamide.
Bicalutamide acts as a potent and highly selective competitive silent antagonist of the androgen receptor (AR). This prevents the activation of the AR and subsequent upregulation of androgen-responsive genes by androgens such as testosterone and dihydrotestosterone (DHT). Bicalutamide has also notably been found to accelerate the degradation of the AR. Owing to its selectivity, unlike steroidal antiandrogens such as cyproterone acetate and megestrol acetate, bicalutamide does not additionally inhibit or suppress androgen production in the body – instead, it exclusively blocks androgen binding and subsequent receptor activation at the level of the AR.
Bicalutamide, unlike flutamide, nilutamide, and enzalutamide, poorly crosses the blood-brain-barrier, and so is limited in its ability to block the actions of androgens in the central nervous system. However, there is possible evidence that the peripheral selectivity of bicalutamide may only be the case in animals (including in rats and dogs) and not in humans, due to species-related differences in drug tissue distribution. In any case, although bicalutamide may cause some sexual difficulties (e.g., erectile dysfunction) and reduced ejaculate volume and sperm count, monotherapy with the drug appears to have minimal effect on sexual desire as well as on sexual activity. These findings support the idea that bicalutamide indeed only minimally crosses the blood-brain-barrier in humans.
Blockade of the AR by bicalutamide in the pituitary gland (which lies outside of the blood-brain-barrier) suppresses the negative feedback of androgens on the release of luteinizing hormone (LH). This, in turn, leads to a significant increase in androgen and estrogen levels. Bicalutamide will more than block the effects of the increased androgen levels in the periphery (monotherapy is still highly effective in the treatment of prostate cancer, to demonstrate), but the effect of the elevated estrogen levels will remain unopposed and lead to feminizing effects, most notably gynecomastia, and the increased levels of androgens will not be blocked in the brain (since bicalutamide only poorly crosses the blood-brain-barrier), which may be considered a benefit or a detriment based on the particular situation (for instance, increased androgen action in the brain might not be desirable to or for some women, while in other individuals, both male and female, effects such as potentially heightened libido may be welcomed).
If bicalutamide is combined with a GnRH analogue or surgical castration, the elevation of androgen and estrogen levels will be prevented and the risks of excessive estrogens, such as gynecomastia, will be reduced. However, since both androgens and estrogens are essential for normal bone metabolism, reducing the anabolic bone effects of both androgens (which increase bone formation by stimulating osteoblasts) and estrogens (which reduce bone resorption by inhibiting osteoclasts) will increase bone loss and promote osteoporosis. In addition, hot flashes, depression, fatigue, and loss of libido are much more likely to occur when bicalutamide is combined with a GnRH analogue.
The activity of bicalutamide lies in the R-isomer, which binds to the AR with an affinity that is about 30-fold higher than that of the S-isomer. The active R-isomer also has a much longer half-life than the S-isomer. At steady-state, serum levels of (R)-bicalutamide are about 100-fold greater than those of (S)-bicalutamide.
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). 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.
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