Bicalutamide

Bicalutamide (marketed as Casodex, Cosudex, Calutide, Kalumid) is an oral non-steroidal anti-androgen used in the treatment of prostate cancer   and hirsutism. It was first launched in 1995 as a combination treatment (with surgical or medical castration) for advanced prostate cancer and subsequently launched as monotherapy for the treatment of earlier stages of the disease.

Bicalutamide is marketed by AstraZeneca with the brand names Casodex and Cosudex. It is recommended 50 mg once daily in combination with a luteinizing hormone-releasing hormone analogue or surgical castration.

Description and mechanism of action
Bicalutamide is an oral non-steroidal anti-androgen with the empirical formula C18H14F4N2O4S and is an off-white powder that is practically insoluble in water.

Bicalutamide acts as a pure anti-androgen by binding to the androgen receptor (AR) and preventing the activation of the AR and subsequent upregulation of androgen responsive genes by androgenic hormones. In addition, bicalutamide accelerates the degradation of the androgen receptor. Bicalutamide has been used as a molecular template for the design of selective androgen receptor modulators (SARMs) such as Andarine and Ostarine.

Indications and use
Bicalutamide is indicated for the treatment of stage D2 metastatic prostate cancer in combination with a luteinizing hormone-releasing hormone analogue or as a monotherapy. It has also been used in clinical trials for ovarian cancer. It has also been used in combination with castration.

Most advanced prostate cancer patients eventually become resistant to antiandrogen including bicalutamide therapy.

Bicalutamide is currently tested for treatment of andogen receptor positive metastatic breast cancer.

Contraindications and precautions
Bicalutamide is contraindicated in patients who have shown a hypersensitivity reaction to its use. Bicalutamide is a teratogen and must not be handled by females who are or may become pregnant. It is known to cause fetal harm. pg8

Caution is required when used together with other medications that depend on CYP3A4 and CYP2D6 metabolisation.

Adverse reactions
Adverse reactions include reproductive system and breast disorders, breast tenderness, gynaecomastia, hot flushes, gastrointestinal disorders, diarrhoea, nausea, hepatic changes (elevated levels of transaminases, jaundice), asthenia and pruritus.

Physiology
Bicalutamide blocks androgen receptors. This prevents testosterone and other androgens from binding to the receptors. Bicalutamide may cause sexual difficulties and a decline in sperm count. Nevertheless bicalutamide monotherapy appears to have minimal effect on sexual activity.

Blockade of androgens receptors by bicalutamide in the brain will eliminate the negative feedback loop of testosterone on the release of luteinizing hormone (LH). This in turn will lead to a dramatic increase in testosterone and estrogen levels. Bicalutamide treatment will block the effects of rising testosterone levels, but the effect of rising estrogen levels will remain unopposed and lead to feminizing effects, the most notable one being gynecomastia, which is often painful.

If bicalutamide is combined with an LHRH agonist or surgical castration then the elevation of estrogen levels will be prevented and the risks of excessive estrogen will be reduced. However, since both testosterone 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.