Pharmacology of bicalutamide

The pharmacology of bicalutamide is the study of the pharmacodynamic and pharmacokinetic properties of the nonsteroidal antiandrogen (NSAA) bicalutamide. In terms of pharmacodynamics, bicalutamide acts as a selective antagonist of the androgen receptor (AR), the biological target of androgens like testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR. It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its AR antagonist activity and can increase androgen, estrogen, and neurosteroid production and levels. This results in a variety of differences of bicalutamide monotherapy compared to surgical and medical castration, such as indirect estrogenic effects and associated benefits like preservation of sexual function and drawbacks like gynecomastia. Bicalutamide can paradoxically stimulate late-stage prostate cancer due to accumulated mutations in the cancer. When used as a monotherapy, bicalutamide can induce breast development in males due to its estrogenic effects. Unlike other kinds of antiandrogens, it may have less adverse effect on the testes and fertility. In terms of pharmacokinetics, bicalutamide is well-absorbed when taken by mouth. However, absorption diminishes at higher dosages. It reaches maximal constant levels after 4 to 12 weeks of therapy. Bicalutamide shows extensive plasma protein binding, mainly to albumin. It crosses the blood–brain barrier and exerts effects in the central nervous system. Bicalutamide is metabolized in the liver by hydroxylation and glucuronidation. The metabolites of bicalutamide are not known to be active. The medication has a very long biological half-life of 6 days with a single dose and 7 to 10 days with repeated administration. Bicalutamide and its metabolites are eliminated in urine, feces, and bile, mainly in the form of conjugates. The pharmacokinetics of bicalutamide are not influenced by food, age, body weight, renal impairment, or mild-to-moderate hepatic impairment, but ethnicity may influence its pharmacokinetics in some cases.

Pharmacodynamics

Antiandrogenic activity

Bicalutamide acts as a highly selective competitive silent antagonist of the androgen receptor (AR) (IC50Tooltip half-maximal inhibitory concentration = 159–243 nM), the major biological target of the androgen sex hormones testosterone and dihydrotestosterone (DHT). It has no capacity to activate the AR under normal physiological circumstances. 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. In terms of relative binding affinity (RBA) for the AR, bicalutamide has shown 0.29 to 6.4%, hydroxyflutamide 0.20 to 1%, flutamide <0.0057%, nilutamide 0.9%, and cyproterone acetate 2.2 to 7.8% of that of metribolone (100%) or DHT (100%) in different studies. In relation to its selectivity for the AR, unlike steroidal antiandrogens (SAAs) such as CPA and megestrol acetate (MGA), bicalutamide does not interact importantly with other steroid hormone receptors (including the ERsTooltip estrogen receptors, PRsTooltip progesterone receptors, GRTooltip glucocorticoid receptor, or MRTooltip mineralocorticoid receptor), and in accordance, has no clinically relevant additional, off-target hormonal activity (estrogenic or antiestrogenic, progestogenic or antiprogestogenic, glucocorticoid or antiglucocorticoid, or mineralocorticoid or antimineralocorticoid). However, it has been reported that bicalutamide has weak affinity for the progesterone receptor (PR) (~100- to 500-fold lower than for the AR), where it acts as an antagonist (with only ~12-fold lower functional inhibition relative to the AR in one study). Hence, bicalutamide may have some antiprogestogenic activity, although the clinical relevance of this is unknown. Bicalutamide does not inhibit 5α-reductase and is not known to inhibit other enzymes involved in androgen steroidogenesis (e.g., CYP17A1). Although bicalutamide does not bind to the ERs, it can increase estrogen levels secondarily to blockade of the AR when used as a monotherapy in males, and for this reason, the medication can indirectly activate the ERs to a degree and hence 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 The affinity of bicalutamide for the AR is approximately 30 to 100 times lower than that of DHT (IC50 ≈ 3.8 nM), the main endogenous ligand of the receptor in the prostate gland. However, sufficiently high relative concentrations of bicalutamide (1,000- to 10,000-fold excess) are able to completely prevent activation of the AR by androgens like DHT and testosterone and subsequent upregulation of the transcription of androgen-responsive genes and associated effects. 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 roughly 600 to 2,500 times higher and at 150 mg/day around 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 approximately 42,000 times higher than testosterone levels at 50 mg/day.

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