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 . It does not decrease androgen levels and has no other important hormonal activity. The medication has progonadotropic effects due to its 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 Bicalutamide and other antiandrogens at the androgen and progesterone receptors (nM) (nM) (%) (nM) (%) 117 157 78 1,819 88 14 26 48 >10,000 12 27 15 83 2,013 90 22 5 75 0.18 96 Notes: values are for functional antagonism. Imax is maximal inhibition. Source: Affinities of bicalutamide at steroid hormone receptors Compound 14–54 3,500–7,200 >1,000,000 44,000–320,000 ≥360,000 0.5–3.1 280–440 38,000–340,000 2,700–20,000 2,100–2,300 Notes: Values are Ki or (nM) for binding inhibition (affinity). Sources:
Antiandrogenic activity
Bicalutamide acts as a highly selective competitive silent antagonist of the androgen receptor (AR) ( = 159–243 nM), the major biological target of the androgen sex hormones testosterone and dihydrotestosterone (DHT). It has no capacity to activate the under normal physiological circumstances. In addition to competitive antagonism of the , bicalutamide has been found to accelerate the degradation of the , 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 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 , unlike steroidal antiandrogens (SAAs) such as and megestrol acetate (MGA), bicalutamide does not interact importantly with other steroid hormone receptors (including the , , , or ), 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 ), where it acts as an antagonist (with only ~12-fold lower functional inhibition relative to the 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 , it can increase estrogen levels secondarily to blockade of the when used as a monotherapy in males, and for this reason, the medication can indirectly activate the to a degree and hence have some indirect estrogenic effects in men. Also in contrast to , 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 .
In addition to the classical nuclear , bicalutamide has also been identified as a potent antagonist of ZIP9, a membrane androgen receptor (mAR) and zinc transporter protein, with an 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 , on the other hand.
Drug levels, androgen levels, and efficacy The affinity of bicalutamide for the is approximately 30 to 100 times lower than that of ( ≈ 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 by androgens like 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.
Whereas testosterone is the major circulating androgen, is the major androgen in the prostate gland. levels in circulation are relatively low and only approximately 10% of those of circulating testosterone levels. Conversely, local concentrations of in the prostate gland are 8- to 10-fold higher than circulating levels of . This is due to high expression of 5α-reductase in the prostate gland, which very efficiently catalyzes the formation of from testosterone such that over 90% of intraprostatic testosterone is converted into . Relative to testosterone, is 2.5- to 10-fold as potent as an agonist in bioassays, and hence, is a much stronger androgen in comparison. As such, 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 gonadotropin-releasing hormone analogues (GnRH analogues), demonstrates a capacity of bicalutamide to strongly antagonize the . On the other hand, analogue monotherapy achieves only a 50 to 60% reduction in levels of in the prostate gland, and combined androgen blockade (CAB), the combination of surgical castration or a analogue and bicalutamide, is significantly more effective than either modality alone in the treatment of prostate cancer. Bicalutamide monotherapy has been found to decrease circulating levels of prostate-specific antigen (), a marker of prostate cancer growth, by 57% at 10 mg/day, 73% at 30 mg/day, 90% at 50 mg/day, 97% at 100 mg/day, and 97% at 150 mg/day, while a 97% reduction in is observed with 50 mg/day bicalutamide as a part of . It has also been reported that bicalutamide monotherapy decreases median circulating levels of at 3 months by 86.7% at 100 mg/day, 91.1% at 150 mg/day, and 93.8% at 200 mg/day (relative to 94–97% for castration). Above a bicalutamide monotherapy dosage of 200 mg/day, up to 600 mg/day, decreases in levels reach a plateau. In a study of very-high-dose bicalutamide monotherapy, decreases in levels after 12weeks were approximately 93% with 300mg/day, 96% with 450mg/day, 96% with 600mg/day, and 96% with castration.
Earlier studies with bicalutamide instead assessed changes in prostatic acid phosphatase (PAP) levels; proportions of patients with decreases of PAP of greater than or equal to 50% were 33% with 10mg/day, 53% with 30mg/day, and 83% with 50mg/day bicalutamide. is a more sensitive and specific prostate cancer tumor marker than PAP and subsequent studies employed .
Despite the high medication levels that are achieved, due to their relatively low affinities for the , it has been suggested that 5 to 10% of may remain unblocked in the prostate gland with using standard doses of first-generation . In accordance, second-generation like enzalutamide and apalutamide, which have 5- to 10-fold higher affinity for the than bicalutamide, have been found to be more effective than bicalutamide in the treatment of prostate cancer. However, in the TERRAIN and STRIVE trials, which compared bicalutamide and enzalutamide as a component of and found that enzalutamide extended life by 3 to 4 times as much time as bicalutamide, the dosage of enzalutamide used (160 mg) was over 3 times that of the dosage of bicalutamide used (50 mg). As a result, it has been suggested that the 50 mg/day dosage of bicalutamide used in this study and in in general may be suboptimal. This is in accordance with clinical findings that decreases with using bicalutamide plateau at a dosage of bicalutamide of 150 to 200 mg/day.
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 medication does not increase testosterone levels in women. For these reasons, much lower dosages of bicalutamide (e.g., 25 mg/day in the hirsutism studies) may be used in women with significant antiandrogenic effectiveness.
Influences on hormone levels
Bicalutamide and testosterone levels in men Dosage Before Aftera Difference Change 10 mg/day 400 ng/dL 490–520 ng/dL +90–120 ng/dL +21–29% 30 mg/day 320 ng/dL 490–550 ng/dL +170–230 ng/dL +55–73% 50 mg/day 370 ng/dL 550–610 ng/dL +180–240 ng/dL +46–62% 100 mg/day 320 ng/dL 460–490 ng/dL +140–170 ng/dL +45–55% 150 mg/day 290 ng/dL 460–490 ng/dL +170–200 ng/dL +60–70% 200 mg/day 320 ng/dL 520–550 ng/dL +200–230 ng/dL +64–73% Footnotes: a = After 29 to 85 days of treatment. Sources: