pharmacology of bicalutamide pharmacology of bicalutamide the pharmacology of bicalutamide, a nonsteroidal antiandrogen (nsaa), has been well-characterized. 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. pharmacology of bicalutamideclinical dataroutes ofadministrationby mouthdrug classnonsteroidal antiandrogenpharmacokinetic databioavailabilitywell-absorbed; absolute bioavailability unknownprotein bindingracemate: 96.1%(r)-isomer: 99.6%(mainly to albumin)metabolismliver (extensively):• hydroxylation (cyp3a4)• glucuronidation (ugt1a9)metabolites• bicalutamide glucuronide• hydroxybicalutamide• hydroxybicalutamide gluc.(all inactive)elimination half-lifesingle-dose: 6 dayscontinuous: 7–10 daysexcretionfeces: 43%urine: 34% 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 antiandrogenarpr-b ki (nm)ic50 (nm)imax (%)ic50 (nm)imax (%) bicalutamide117157781,81988 cyproterone acetate142648>10,00012 hydroxyflutamide2715832,01390 mifepristone225750.1896 notes: ic50 values are for functional antagonism. imax is maximal inhibition. source: affinities of bicalutamide at steroid hormone receptors compoundarprergrmr bicalutamide14–543,500–7,200>1,000,00044,000–320,000≥360,000 dihydrotestosterone0.5–3.1280–44038,000–340,0002,700–20,0002,100–2,300 notes: values are ki or ic50 (nm) for binding inhibition (affinity). sources: antiandrogenic activity crystal structure of w741l (pos. 741, w➞l) mutant ar lbd and (r)-bicalutamide protein–ligand complex. affinities compound rba metribolone 100 dihydrotestosterone 85 cyproterone acetate 7.8 bicalutamide 1.4 nilutamide 0.9 hydroxyflutamide 0.57 flutamide <0.0057 notes: at androgen receptors; measured in human prostate tissue. relative to metribolone, which is by definition 100% relative potencies of selected antiandrogens antiandrogenrelative potency bicalutamide4.3 hydroxyflutamide3.5 flutamide3.3 cyproterone acetate1.0 zanoterone0.4 description: relative potencies of orally administered antiandrogens in antagonizing 0.8 to 1.0 mg/kg s.c. testosterone propionate-induced ventral prostate weight increase in castrated immature male rats. higher values mean greater potency. sources: see template. androgen receptor antagonistic potency of spironolactone, cyproterone acetate, and flutamide in castrated male rats treated with exogenous testosterone (as measured by inhibition of androgen-dependent ventral prostate weight). bicalutamide is a much more potent androgen receptor antagonist than flutamide both in animals and in humans. bicalutamide acts as a highly selective competitive silent antagonist of the androgen receptor (ar) (ic50 = 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 relation to its selectivity for the ar, unlike steroidal antiandrogens (saas) such as cyproterone acetate (cpa) and megestrol acetate, bicalutamide does not interact importantly with other steroid hormone receptors (including the ers, prs, gr, or mr), 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. relative affinities of first-generation nonsteroidal antiandrogens for the androgen receptor speciesic50 (nm)rba (ratio) bicalutamide2-hydroxyflutamidenilutamidebica / 2-oh-flubica / niluref rat190700nd4.0nd rat~400~900~9002.32.3 ratndndnd3.3nd rata35954565186201.35.2 human~300~700~5002.51.6 human~100~300nd~3.0nd humana2490234553001.02.1 footnotes: a = controversial data. sources: see template. 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. median psa reduction (%) with bicalutamide monotherapy at different dosages (mg/day) and with castration monotherapy. whereas testosterone is the major circulating androgen, dht is the major androgen in the prostate gland. dht levels in circulation are relatively low and only approximately 10% of those of circulating testosterone levels. conversely, local concentrations of dht in the prostate gland are 8- to 10-fold higher than circulating levels of dht. this is due to high expression of 5α-reductase in the prostate gland, which very efficiently catalyzes the formation of dht from testosterone such that over 90% of intraprostatic testosterone is converted into dht. relative to testosterone, dht is 2.5- to 10-fold as potent as an ar agonist in bioassays, and hence, is a much stronger androgen in comparison. as such, ar 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 ar. on the other hand, gnrh analogue monotherapy achieves only a 50 to 60% reduction in levels of dht in the prostate gland, and combined androgen blockade (cab), the combination of surgical castration or a gnrh 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 (psa), 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 psa is observed with 50 mg/day bicalutamide as a part of cab. it has also been reported that bicalutamide monotherapy decreases median circulating levels of psa 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 psa levels reach a plateau. in a study of very-high-dose bicalutamide monotherapy, decreases in psa levels after 12 weeks were approximately 93% with 300 mg/day, 96% with 450 mg/day, 96% with 600 mg/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 10 mg/day, 53% with 30 mg/day, and 83% with 50 mg/day bicalutamide. psa is a more sensitive and specific prostate cancer tumor marker than pap and subsequent studies employed psa. despite the high medication levels that are achieved, due to their relatively low affinities for the ar, it has been suggested that 5 to 10% of dht may remain unblocked in the prostate gland with cab using standard doses of first-generation nsaas. in accordance, second-generation nsaas like enzalutamide and apalutamide, which have 5- to 10-fold higher affinity for the ar 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 cab 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 cab in general may be suboptimal. this is in accordance with clinical findings that psa decreases with cab 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, the hypothalamic–pituitary–glandular axes, and sex hormone production. bicalutamide and testosterone levels in men dosagebeforeafteradifferencechange 10 mg/day400 ng/dl490–520 ng/dl+90–120 ng/dl+21–29% 30 mg/day320 ng/dl490–550 ng/dl+170–230 ng/dl+55–73% 50 mg/day370 ng/dl550–610 ng/dl+180–240 ng/dl+46–62% 100 mg/day320 ng/dl460–490 ng/dl+140–170 ng/dl+45–55% 150 mg/day290 ng/dl460–490 ng/dl+170–200 ng/dl+60–70% 200 mg/day320 ng/dl520–550 ng/dl+200–230 ng/dl+64–73% footnotes: a = after 29 to 85 days of treatment. sources: in men, blockade of the ar by bicalutamide in the pituitary gland and hypothalamus prevents the negative feedback of androgens on the hypothalamic–pituitary–gonadal (hpg) axis, resulting in an increase in luteinizing hormone (lh) secretion and levels. follicle-stimulating hormone (fsh) levels, in contrast, remain essentially unchanged. the increase in lh levels leads to an elevation in androgen and estrogen levels. at a dosage of 150 mg/day, bicalutamide has been found to increase testosterone levels by about 1.5- to 2-fold (59–97% increase) and estradiol levels by about 1.5- to 2.5-fold (65–146% increase). levels of dht are also increased to a lesser extent (by 24–30%), and concentrations of sex hormone-binding globulin (shbg) and prolactin increase as well (by 8–42% and 40–65%, respectively) secondary to the increase in estradiol levels. the estradiol concentrations produced in men by bicalutamide monotherapy are said to approximate the low-normal estradiol levels of a premenopausal woman, while testosterone levels generally remain in the high end of the normal male range and rarely exceed it. dosages of bicalutamide of 10 mg, 30 mg, and 50 mg per day have been found