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Bicalutamide

August 23, 2023

Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer.[10] It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC).[11][10][12] To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration.[4][2][13] Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings.[13][14][15][16] Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women,[17][18] as a puberty blocker and component of feminizing hormone therapy for transgender girls and women,[19] to treat gonadotropin-independent early puberty in boys,[20] and to prevent overly long-lasting erections in men.[21] It is taken by mouth.[10]

Bicalutamide
Clinical data
PronunciationBicalutamide:
• /ˌbaɪkəˈluːtəmaɪd/[1]
• BY-kə-LOO-tə-myde[1]
Trade namesCasodex, Calutex, others
Other namesICI-176,334; ZD-176,334
AHFS/Drugs.comMonograph
MedlinePlusa697047
License data
Pregnancy
category
  • AU: D
Routes of
administration		By mouth[2]
Drug classNonsteroidal antiandrogen
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
BioavailabilityWell-absorbed; absolute bioavailability unknown[3]
Protein bindingRacemate: 96.1%[2]
(R)-Isomer: 99.6%[2]
(Mainly to albumin)[2]
MetabolismLiver (extensively):[4][9]
• Hydroxylation (CYP3A4)
• Glucuronidation (UGT1A9)
Metabolites• Bicalutamide glucuronide
• Hydroxybicalutamide
• Hydroxybicalutamide gluc.
(All inactive)[4][2][5][6]
Elimination half-lifeSingle-dose: 5.8 days[7]
Continuous: 7–10 days[8]
ExcretionFeces: 43%[4]
Urine: 34%[4]
Identifiers
  • (RS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide
CAS Number
  • 90357-06-5 Y
    113299-40-4 ((R)-isomer)
    113299-38-0 ((S)-isomer)
PubChem CID
  • 2375
IUPHAR/BPS
  • 2863
DrugBank
  • DB01128 Y
ChemSpider
  • 2284 Y
UNII
  • A0Z3NAU9DP
KEGG
  • C08160 Y
ChEBI
  • CHEBI:91617 Y
ChEMBL
  • ChEMBL409 Y
PDB ligand
  • 198 (PDBe, RCSB PDB)
CompTox Dashboard (EPA)
  • DTXSID2022678
ECHA InfoCard100.126.100
Chemical and physical data
FormulaC18H14F4N2O4S
Molar mass430.37 g·mol−1
3D model (JSmol)
  • Interactive image
ChiralityRacemic mixture (of (R)- and (S)-enantiomers)
Melting point191 to 193 °C (376 to 379 °F) (experimental)
Boiling point650 °C (1,202 °F) (predicted)
Solubility in water0.005
  • CC(O)(CS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
  • InChI=1S/C18H14F4N2O4S/c1-17(26,10-29(27,28)14-6-3-12(19)4-7-14)16(25)24-13-5-2-11(9-23)15(8-13)18(20,21)22/h2-8,26H,10H2,1H3,(H,24,25) Y
  • Key:LKJPYSCBVHEWIU-UHFFFAOYSA-N Y
  (verify)

Common side effects of bicalutamide in men include breast growth, breast tenderness, and hot flashes.[10] Other side effects in men include feminization and sexual dysfunction.[22][23] Some side effects like breast changes and feminization are minimal when combined with castration.[24] While the medication appears to produce few side effects in women, its use in women is not explicitly approved by the Food and Drug Administration (FDA) at this time.[25][10] Use during pregnancy may harm the baby.[10] In men with early prostate cancer, bicalutamide monotherapy has been found to increase the likelihood of death from causes other than prostate cancer.[26][13] Bicalutamide produces abnormal liver changes necessitating discontinuation in around 1% of people.[27][13] Rarely, it has been associated with cases of serious liver damage,[10] serious lung toxicity,[3] and sensitivity to light.[28][29] Although the risk of adverse liver changes is small, monitoring of liver function is recommended during treatment.[10]

Bicalutamide is a member of the nonsteroidal antiandrogen (NSAA) group of medications.[3] It works by selectively blocking the androgen receptor (AR), the biological target of the androgen sex hormones testosterone and dihydrotestosterone (DHT).[30] It does not lower androgen levels.[3] The medication can have some estrogen-like effects in men when used as a monotherapy due to increased estradiol levels.[31][32][33] Bicalutamide is well-absorbed, and its absorption is not affected by food.[2] The elimination half-life of the medication is around one week.[2][10] It shows peripheral selectivity in animals, but crosses the blood–brain barrier and affects both the body and brain in humans.[2][34]

Bicalutamide was patented in 1982 and approved for medical use in 1995.[35] It is on the World Health Organization's List of Essential Medicines.[36] Bicalutamide is available as a generic medication.[37] The drug is sold in more than 80 countries, including most developed countries.[38][39][40] It was at one time the most widely used antiandrogen in the treatment of prostate cancer, with millions of men with the disease having been prescribed it.[23][41][42][43][44] Although bicalutamide is also used for other indications besides prostate cancer, the vast majority of prescriptions appear to be for treatment of prostate cancer.[44]

Medical uses

Main article: Medical uses of bicalutamide

Bicalutamide is approved for and mainly used in the following indications:[45]

In Japan, bicalutamide is uniquely used at a dosage of 80 mg/day both in combination with castration and as a monotherapy in the treatment of prostate cancer.[48][49]

Bicalutamide is also employed for the following off-label (non-approved) indications:

The medication has been suggested for but has uncertain effectiveness in the following indication:

For more information on these uses, see the medical uses of bicalutamide article.

Available forms

Bicalutamide is available for the treatment of prostate cancer in most developed countries,[80][38][81] including over 80 countries worldwide.[39][40] It is available in 50 mg, 80 mg (in Japan),[48] and 150 mg tablets for oral administration.[82][83] The drug is registered for use as a 150 mg/day monotherapy for the treatment of LAPC in at least 55 countries,[2] with the U.S. being a notable exception where it is registered only for use at a dosage of 50 mg/day in combination with castration.[84] No other formulations or routes of administration are available or used.[82] All formulations of bicalutamide are specifically indicated for the treatment of prostate cancer alone or in combination with surgical or medication castration.[4] Due to the low water solubility of bicalutamide, bicalutamide in oral bicalutamide tablets is micronized to ensure small and consistent particle sizes and optimize oral bioavailability.[85][2]

A combined formulation of bicalutamide and the GnRH agonist goserelin in which goserelin is provided as a subcutaneous implant for injection and bicalutamide is included as 50 mg tablets for oral ingestion is marketed in Australia and New Zealand under the brand name ZolaCos CP (Zoladex–Cosudex Combination Pack).[81][86][87][88]

Contraindications

Bicalutamide is pregnancy category X, or "contraindicated in pregnancy", in the U.S.,[27] and pregnancy category D, the second most restricted rating, in Australia.[89] As such, it is contraindicated in women during pregnancy, and women who are sexually active and who can or may become pregnant are strongly recommended to take bicalutamide only in combination with adequate contraception.[90][91] It is unknown whether bicalutamide is excreted in breast milk, but many drugs are excreted in breast milk, and for this reason, bicalutamide treatment is similarly not recommended while breastfeeding.[3][27]

In individuals with severe, though not mild-to-moderate hepatic impairment, there is evidence that the elimination of bicalutamide is slowed, and hence, caution may be warranted in these patients as circulating levels of bicalutamide may be increased.[2][92] In severe hepatic impairment, the elimination half-life of the active (R)-enantiomer of bicalutamide is increased by about 1.75-fold (76% increase; elimination half-life of 5.9 and 10.4 days for normal and impaired patients, respectively).[13][93][94] The elimination half-life of bicalutamide is unchanged in renal impairment.[84]

Side effects

Main article: Side effects of bicalutamide
Major side effects of bicalutamide[95][96][97][98][99][100][101]
Frequency Class of effect Effect
Very common (≥10%) Reproductive system and breast disorders • Breast tenderness[a]
• Gynecomastia[a]
Common (1–10%) General and psychiatric disorders • Asthenia
• Decreased libido
• Erectile dysfunction
• Hot flashes
Skin and subcutaneous
tissue disorders 		• Decreased body hair
Hepato-biliary disorders • Elevated liver enzymes[b]
Uncommon (0.1–1%) Immune system disorders and hypersensitivity reactions • Angioedema
• Hives
Rare (<0.1%) or unknown Respiratory disorders • Lung disease[c]
Skin and subcutaneous tissue disorders • Sensitivity to light
Hepato-biliary disorders • Liver toxicity[c]
  1. ^ a b May occur as often as 90% of those taking bicalutamide, but is mild-to-moderate in 90% of occurrences. Incidence greatly decreased in combination with castration.
  2. ^ Usually transient, rarely severe. Resolves or improves with continued therapy or on discontinuation.
  3. ^ a b Reported in single cases, but not observed in any large, randomized trial. With regular liver monitoring and discontinuation as needed.

The side effect profile of bicalutamide is highly dependent on sex; that is, on whether the person is male or female. In men, due to androgen deprivation, a variety of side effects of varying severity may occur during bicalutamide treatment, with breast pain/tenderness and gynecomastia (breast development/enlargement) being the most common.[102][103] Gynecomastia occurs in up to 80% of men treated with bicalutamide monotherapy, and is of mild-to-moderate severity in more than 90% of affected men.[103][104] In addition to breast changes, physical feminization and demasculinization in general, including reduced body hair growth, decreased muscle mass and strength, feminine changes in fat mass and distribution, reduced penile length, and decreased semen/ejaculate volume, may occur in men.[102][105][22][106] Other side effects that have been observed in men and that are similarly related to androgen deprivation include hot flashes, sexual dysfunction (e.g., loss of libido, erectile dysfunction), depression, fatigue, weakness, and anemia.[102][107][108] However, most men have preserved sexual function with bicalutamide monotherapy.[109][110] In females, due to the minimal biological importance of androgens in this sex,[111][112] the side effects of pure antiandrogens or NSAAs are few, and bicalutamide has been found to be very well tolerated.[25] However, bicalutamide has been found to increase levels of total and LDL cholesterol in women.[113][114][57] The non-pharmacological side-effect profile of bicalutamide (i.e., side effects not related to its antiandrogenic activity) is said to be similar to that with placebo.[115] In any case, general side effects of bicalutamide that might occur in either sex include diarrhea, constipation, abdominal pain, nausea, dry skin, itching, and rash.[107][3][116][117][118][119] The drug is well-tolerated at higher dosages than 50 mg/day, up to 600 mg/day, with rare additional side effects.[84][120][121]

Bicalutamide has been associated with abnormal liver function tests such as elevated liver enzymes.[107][13] In the Early Prostate Cancer (EPC) clinical programme of bicalutamide for LPC and LAPC, the rate of abnormal liver function tests with bicalutamide monotherapy was 3.4% relative to 1.9% for placebo.[13][122] However, higher rates, up to 11%, have been seen in other studies.[18][27] Hepatic changes that have necessitated discontinuation of bicalutamide, such as marked increases in liver enzymes or hepatitis, have occurred in 0.3 to 1.5% of men in clinical trials, or approximately 1% overall.[27][13][33][122][123] Elevated liver enzymes with bicalutamide usually occur within the first 3 to 6 months of treatment.[107][27] Monitoring of liver function during treatment is recommended, particularly in the first few months.[13][102] In men with early prostate cancer, bicalutamide monotherapy has been found to increase non-prostate cancer mortality.[26][124][13] The reasons for the increase in mortality with bicalutamide in these men are unknown, but possible factors could include androgen deprivation or drug-related toxicity of bicalutamide.[125][126]

There are 10 published case reports of liver toxicity associated with bicalutamide as of 2022.[127][128][129][130] Death occurred in 2 of these cases.[127][131][132] Hundreds of additional cases of liver complications in people taking bicalutamide exist in the FDA Adverse Event Reporting System (FAERS) database.[133] In all of the published case reports of liver toxicity with bicalutamide, the onset of symptoms was within the first 6 months of treatment.[128][129][130] Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice.[27] There are also published case reports of interstitial pneumonitis and eosinophilic lung disease associated with bicalutamide.[134][135][136] along with hundreds of additional instances in the FAERS database as well.[133] Interstitial pneumonitis can potentially progress to pulmonary fibrosis and may be fatal. Symptoms that may indicate lung dysfunction include dyspnea (difficult breathing or shortness of breath), cough, and pharyngitis (inflammation of the pharynx, resulting in sore throat).[137] The exact incidence of liver toxicity and interstitial pneumonitis with bicalutamide are unknown, but both are said to be very rare events.[129][138][139] A few cases of photosensitivity have been reported with bicalutamide.[28] Hypersensitivity reactions (drug allergy) like angioedema and hives have also uncommonly been reported in association with bicalutamide.[27]

Because it is an antiandrogen, bicalutamide has a theoretical risk of birth defects like ambiguous genitalia in male fetuses.[90][91][140][141] Due to its teratogenic capacity, contraception should be used in women taking bicalutamide who are fertile and sexually active.[142]

Comparison

See also: Comparison of bicalutamide with other antiandrogens

The side effect profile of bicalutamide in men and women differs from that of other antiandrogens and is considered favorable in comparison.[143][110][144][145] Relative to GnRH analogues and the steroidal antiandrogen (SAA) cyproterone acetate (CPA), bicalutamide monotherapy has a much lower incidence and severity of hot flashes and sexual dysfunction.[109][110][104][146] In addition, unlike GnRH analogues and CPA, bicalutamide monotherapy is not associated with decreased bone mineral density or osteoporosis.[104][110] Conversely, bicalutamide monotherapy is associated with much higher rates of breast tenderness, gynecomastia, and feminization in men than GnRH analogues and CPA.[104] However, gynecomastia with bicalutamide is rarely severe and discontinuation rates due to this side effect are fairly low.[104][110] These differences in side effects between bicalutamide monotherapy, GnRH analogues, and CPA are attributed to the fact that whereas GnRH analogues and CPA suppress estrogen production, bicalutamide monotherapy does not lower estrogen levels and in fact actually increases them.[104]

Bicalutamide does not share the risk of neuropsychiatric side effects like fatigue as well as cardiovascular side effects like coagulation changes, blood clots, fluid retention, ischemic cardiomyopathy, and adverse serum lipid changes that CPA has been associated with.[146][147][148][149] It has a much lower risk of hepatotoxicity than flutamide and CPA and of interstitial pneumonitis than nilutamide.[150][110][131][151][152][153] The drug also does not share the unique risks of diarrhea with flutamide and nausea, vomiting, visual disturbances, and alcohol intolerance with nilutamide.[110][146][151] Unlike enzalutamide, bicalutamide is not associated with seizures or related central side effects like anxiety and insomnia.[154][155] However, although the risk of adverse liver changes with bicalutamide is low, enzalutamide differs from bicalutamide in having no known risk of elevated liver enzymes or hepatotoxicity.[156][157] In contrast to the SAA spironolactone, bicalutamide does not have antimineralocorticoid effects,[158] and hence is not associated with hyperkalemia, urinary frequency, dehydration, hypotension, or other related side effects.[159][160][161][146] In women, unlike CPA and spironolactone, bicalutamide does not produce menstrual irregularity or amenorrhea and does not interfere with ovulation or fertility.[52][162]

Overdose

A single oral dose of bicalutamide in humans that results in symptoms of overdose or that is considered to be life-threatening has not been established.[27][163] Dosages of up to 600 mg/day have been well tolerated in clinical trials,[164] and it is notable that there is a saturation of absorption with bicalutamide such that circulating levels of its active (R)-enantiomer do not further increase above a dosage of 300 mg/day.[2][164] Overdose is considered unlikely to be life-threatening with bicalutamide or other first-generation NSAAs (i.e., flutamide and nilutamide).[165] A massive overdose of nilutamide (13 grams, or 43 times the normal maximum 300 mg/day clinical dosage) in a 79-year-old man was uneventful, producing no clinical signs, symptoms, or toxicity.[166] There is no specific antidote for bicalutamide or NSAA overdose, and treatment should be based on symptoms, if any are present.[27][163]

Interactions

Bicalutamide is almost exclusively metabolized by CYP3A4.[4] As such, its levels in the body may be altered by inhibitors and inducers of CYP3A4.[7] (For a list of CYP3A4 inhibitors and inducers, see here.) However, in spite of the fact bicalutamide is metabolized by CYP3A4, there is no evidence of clinically significant drug interactions when bicalutamide at a dosage of 150 mg/day or less is co-administered with drugs that inhibit or induce cytochrome P450 enzyme activity.[13]

In-vitro studies suggest that bicalutamide may be able to inhibit CYP3A4 and, to a lesser extent, CYP2C9, CYP2C19, and CYP2D6.[2] Conversely, animal studies suggest that bicalutamide may induce cytochrome P450 enzymes.[2] In a clinical study, bicalutamide co-administered with the CYP3A4 substrate midazolam caused only a small and statistically non-significant increase in midazolam levels (+27%) presumably due to CYP3A4 inhibition.[2] However, this was well below increases in midazolam exposure with potent CYP3A4 inhibitors like ketoconazole (+1500%), itraconazole (+1000%), and erythromycin (+350%), and is considered to not be clinically important.[2] There is no indication of clinically significant enzyme inhibition or induction with bicalutamide at doses of 150 mg/day or below.[2]

Because bicalutamide circulates at relatively high concentrations and is highly protein-bound, it has the potential to displace other highly protein-bound drugs like warfarin, phenytoin, theophylline, and aspirin from plasma binding proteins.[103][107] This could, in turn, result in increased free concentrations of such drugs and increased effects and/or side effects, potentially necessitating dosage adjustments.[103] Bicalutamide has specifically been found to displace coumarin anticoagulants like warfarin from their plasma binding proteins (namely albumin) in vitro, potentially resulting in an increased anticoagulant effect, and for this reason, close monitoring of prothrombin time and dosage adjustment as necessary is recommended when bicalutamide is used in combination with these drugs.[167][168][169] However, in spite of this, no conclusive evidence of an interaction between bicalutamide and other drugs was found in clinical trials of nearly 3,000 patients.[107]

Pharmacology

Pharmacodynamics

Main article: Pharmacology of bicalutamide § Pharmacodynamics

Antiandrogenic activity

Bicalutamide acts as a highly selective competitive silent antagonist of the AR (IC50 = 159–243 nM), the major biological target of the androgen sex hormones testosterone and DHT, and hence is an antiandrogen.[30][170][171][172] The activity of bicalutamide lies in the (R)-isomer.[173] Due to its selectivity for the AR, bicalutamide does not interact importantly with other steroid hormone receptors and hence has no clinically relevant off-target hormonal activity (e.g., progestogenic, estrogenic, glucocorticoid, antimineralocorticoid).[174][34][173][45] However, it has been reported that bicalutamide has weak affinity for the progesterone receptor (PR), where it is an antagonist, and hence it could have some antiprogestogenic activity.[175] Bicalutamide does not inhibit 5α-reductase nor is known to inhibit other enzymes involved in androgen steroidogenesis (e.g., CYP17A1).[176] Although it does not bind to the estrogen receptors (ERs), bicalutamide can increase estrogen levels secondarily to AR blockade when used as a monotherapy in males, and hence can have some indirect estrogenic effects in males.[177] Bicalutamide neither suppresses nor inhibits androgen production in the body (i.e., it does not act as an antigonadotropin or androgen steroidogenesis inhibitor or lower androgen levels) and hence exclusively mediates its antiandrogenic effects by antagonizing the AR.[3][174][173] In addition to the classical nuclear AR, bicalutamide has been assessed at the membrane androgen receptors (mARs) and found to act as a potent antagonist of ZIP9 (IC50 = 66.3 nM), whereas it does not appear to interact with GPRC6A.[178][179]

The affinity of bicalutamide for the AR is relatively low as it is approximately 30 to 100 times lower than that of DHT, which is 2.5- to 10-fold as potent as an AR agonist as testosterone in bioassays and is the main endogenous ligand of the receptor in the prostate gland.[180][172][2][181] However, typical clinical dosages of bicalutamide result in circulating levels of the drug that are thousands of times higher than those of testosterone and DHT, allowing it to powerfully prevent them from binding to and activating the receptor.[182][183][34][184][27][89][185][13][186] This is especially true in the case of surgical or medical castration, in which testosterone levels in the circulation are approximately 95% reduced and DHT levels in the prostate gland are about 50 to 60% reduced.[172][187] In women, levels of testosterone are substantially lower (20- to 40-fold) than in men,[188] so much smaller doses of bicalutamide (e.g., 25 mg/day in the hirsutism studies) are necessary.[17][52][189][33]

Blockade of the AR by bicalutamide in the pituitary gland and hypothalamus results in prevention of the negative feedback of androgens on the hypothalamic–pituitary–gonadal axis (HPG axis) in males and consequent disinhibition of pituitary luteinizing hormone (LH) secretion.[109] This, in turn, results in an increase in circulating LH levels and activation of the gonadal production of testosterone and by extension production of estradiol.[190] Levels of testosterone have been found to increase 1.5- to 2-fold (59–97% increase) and levels of estradiol about 1.5- to 2.5-fold (65–146% increase) in men treated with 150 mg/day bicalutamide monotherapy.[31][32][33] In addition to testosterone and estradiol, there are smaller increases in concentrations of DHT, sex hormone-binding globulin, and prolactin.[33] Estradiol levels with bicalutamide monotherapy are similar to those in the low-normal premenopausal female range while testosterone levels generally remain in the high end of the normal male range.[32][191][174] Testosterone concentrations do not typically exceed the normal male range due to negative feedback on the HPG axis by the increased concentrations of estradiol.[109] Bicalutamide influences the HPG axis and increases hormone levels only in men and not also in women.[192][193][194] This is due to the much lower levels of androgens in women and their lack of basal suppression of the HPG axis in this sex.[192][193][194] As evidenced by its effectiveness in the treatment of prostate cancer and other androgen-dependent conditions, the antiandrogenic actions of bicalutamide considerably exceed any impact of the increased levels of testosterone it results in.[84] However, the elevated levels of estradiol remain unopposed by bicalutamide and are responsible for the gynecomastia and feminizing side effects it causes in men.[195] Although bicalutamide monotherapy increases gonadotropin and sex hormone levels in men, this will not occur if bicalutamide is combined with an antigonadotropin such as a GnRH analogue, estrogen, or progestogen, as these medications maintain negative feedback on the HPG axis.[50][196][197]

NSAA monotherapy, including with bicalutamide, shows a number of tolerability differences from methods of androgen deprivation therapy that incorporate surgical or medical castration. For example, the rates of hot flashes, depression, fatigue, and sexual dysfunction are all much higher with GnRH analogues than with NSAA monotherapy. It is thought that this is because GnRH analogues suppress estrogen production in addition to androgen production, resulting in estrogen deficiency.[198][199][200] In contrast, NSAA monotherapy does not decrease estrogen levels and in fact increases them, resulting in an excess of estrogens that compensates for androgen deficiency and allows for a preservation of mood, energy, and sexual function.[198][199][200] Neurosteroids that are produced from testosterone like 3α-androstanediol and 3β-androstanediol, which are ERβ agonists and the former a potent GABAA receptor positive allosteric modulator, may also be involved.[201][202][203][204][205][206][207] In the specific case of sexual dysfunction, an additional possibility for the difference is that without concomitant suppression of androgen production, blockade of the AR by the bicalutamide in the brain is incomplete and insufficient to markedly influence sexual function.[citation needed]

Under normal circumstances, bicalutamide has no capacity to activate the AR.[208][209] However, in prostate cancer, mutations and overexpression of the AR can accumulate in prostate gland cells which can convert bicalutamide from an antagonist of the AR into an agonist.[208][210] This can result in paradoxical stimulation of prostate cancer growth with bicalutamide and is responsible for the phenomenon of the antiandrogen withdrawal syndrome, where antiandrogen discontinuation paradoxically slows the rate of prostate cancer growth.[208][210]

In transgender women, breast development is a desired effect of antiandrogen or estrogen treatment.[63][211] Breast development and gynecomastia induced by bicalutamide is thought to be mediated by increased activation of the ER secondary to blockade of the AR (resulting in disinhibition of the ER in breast tissue) and increased levels of estradiol.[20][212][213] In addition to fat deposition, connective tissue growth, and ductal development, bicalutamide has been found to produce moderate lobuloalveolar development of the breasts.[214][215][216] However, full lobuloalveolar maturation necessary for lactation and breastfeeding will not occur without progestogen treatment.[214][215][216]

Bicalutamide monotherapy seems to have minimal effect on testicular spermatogenesis, testicular ultrastructure, and certain aspects of male fertility.[217][90][218] This seems to be because testosterone levels in the testes (where ~95% of testosterone in males is produced) are extremely high (up to 200-fold higher than circulating levels) and only a small fraction (less than 10%) of the normal levels of testosterone in the testes are actually necessary to maintain spermatogenesis.[219][220][221] As a result, bicalutamide appears to not be able to compete with testosterone in this sole part of the body to an extent sufficient to considerably interfere with androgen signaling and function.[219][220][221] However, while bicalutamide does not seem to be able to adversely influence testicular spermatogenesis, it may interfere with AR-dependent sperm maturation and transport outside of the testes in the epididymides and vas deferens where androgen levels are far lower, and hence may still be able to impair male fertility.[222] In addition, the combination of bicalutamide with other medications, such as estrogens, progestogens, and GnRH analogues, can compromise spermatogenesis due to their own adverse effects on male fertility.[223][224][225][226][227][228] These medications are able to strongly suppress gonadal androgen production, which can severely impair or abolish testicular spermatogenesis, and estrogens also appear to have direct and potentially long-lasting cytotoxic effects in the testes at sufficiently high concentrations.[223][224][225][226][227][228]

Other activities

Bicalutamide has been found to act as an inhibitor or inducer of certain cytochrome P450 enzymes including CYP3A4, CYP2C9, CYP2C19, and CYP2D6 in preclinical research, but no evidence of this has been found in humans treated with up to 150 mg/day.[2] It has also been identified in vitro as a strong inhibitor of CYP27A1 (cholesterol 27-hydroxylase) and as an inhibitor of CYP46A1 (cholesterol 24-hydroxylase), but this has yet to be assessed or confirmed in vivo or in humans and the clinical significance remains unknown.[229][230] Bicalutamide has been found to be a P-glycoprotein (ABCB1) inhibitor.[231][232][233] Like other first-generation NSAAs and enzalutamide, it has been found to act as a weak non-competitive inhibitor of GABAA receptor-mediated currents in vitro (IC50 = 5.2 μM).[234][235] However, unlike enzalutamide, bicalutamide has not been found to be associated with seizures or other related adverse central effects, so the clinical relevance of this finding is uncertain.[234][235]

Pharmacokinetics

Main article: Pharmacology of bicalutamide § Pharmacokinetics

Though its absolute bioavailability in humans is unknown, bicalutamide is known to be extensively and well-absorbed.[2][3] Its absorption is not affected by food.[3][167] The absorption of bicalutamide is linear at doses up to 150 mg/day and is saturable at doses above this, with no further increases in steady-state levels of bicalutamide occurring at doses above 300 mg/day.[2][13][236][164] Whereas absorption of (R)-bicalutamide is slow, with levels peaking at 31 to 39 hours after a dose, (S)-bicalutamide is much more rapidly absorbed.[13][27][2] Steady-state concentrations of the drug are reached after 4 to 12 weeks of treatment independently of dosage, with a 10- to 20-fold progressive accumulation in levels of (R)-bicalutamide.[13][237][238][185] The long time to steady-state levels is the result of bicalutamide's very long elimination half-life.[185] There is wide interindividual variability in (R)-bicalutamide levels (up to 16-fold) with bicalutamide regardless of dosage.[2]

The tissue distribution of bicalutamide is not well-characterized.[239] The amount of bicalutamide in semen that could potentially be transferred to a female partner during sexual intercourse is low and is not thought to be important.[89] Based on animal studies with rats and dogs it was thought that bicalutamide could not cross the blood–brain barrier and hence could not enter the brain.[240][34][241][242] As such, it was initially thought to be a peripherally selective antiandrogen.[240][34] However, subsequent clinical studies found that this was not also the case for humans, indicating species differences; bicalutamide crosses into the human brain and, in accordance, produces effects and side effects consistent with central antiandrogenic action.[2][109][243][244][245] In any case, there is indication that bicalutamide might have at least some peripheral selectivity in humans.[246] Bicalutamide is highly plasma protein bound (96.1% for racemic bicalutamide, 99.6% for (R)-bicalutamide) and is bound mainly to albumin, with negligible binding to SHBG and corticosteroid-binding globulin.[4][2][239][176]

Bicalutamide is metabolized in the liver.[4][167] (R)-Bicalutamide is metabolized slowly and almost exclusively via hydroxylation by CYP3A4 into (R)-hydroxybicalutamide.[167][2][4][247] This metabolite is then glucuronidated by UGT1A9.[167][2][9][6] In contrast to (R)-bicalutamide, (S)-bicalutamide is metabolized rapidly and mainly by glucuronidation (without hydroxylation).[167] None of the metabolites of bicalutamide are known to be active and levels of the metabolites are low in plasma, where unchanged biclautamide predominates.[4][5][2] Due to the stereoselective metabolism of bicalutamide, (R)-bicalutamide has a far longer terminal half-life than (S)-bicalutamide and its levels are about 10- to 20-fold higher in comparison following a single dose and 100-fold higher at steady-state.[13][247][248] (R)-Bicalutamide has a relatively long elimination half-life of 5.8 days with a single dose and 7 to 10 days following repeated administration.[8]

Bicalutamide is eliminated in similar proportions in feces (43%) and urine (34%), while its metabolites are eliminated roughly equally in urine and bile.[4][167][249][250] The drug is excreted to a substantial extent in unmetabolized form, and both bicalutamide and its metabolites are eliminated mainly as glucuronide conjugates.[173] The glucuronide conjugates of bicalutamide and its metabolites are eliminated from the circulation rapidly, unlike unconjugated bicalutamide.[2][167][251]

The pharmacokinetics of bicalutamide are not affected by consumption of food, a person's age or body weight, renal impairment, or mild-to-moderate hepatic impairment.[2][185] However, steady-state levels of bicalutamide are higher in Japanese individuals than in white people.[2]

Bicalutamide metabolism in humans[2][9]
 
Bicalutamide
(S)-Bicalutamide glucuronide
(R)-Hydroxybicalutamide
(R)-Hydroxybicalutamide glucuronide
via UGT1A9
via UGT1A9
via CYP3A4
 
This diagram illustrates the primary metabolic pathways involved in the metabolism of bicalutamide in humans.

Chemistry

Bicalutamide is a racemic mixture consisting of equal proportions of enantiomers (R)-bicalutamide (dextrorotatory) and (S)-bicalutamide (levorotatory).[27] Its systematic name (IUPAC) is (RS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide.[252][253] The compound has a chemical formula of C18H14F4N2O4S, a molecular weight of 430.373 g/mol, and is a fine white to off-white powder.[27][89]

The acid dissociation constant (pKa') of bicalutamide is approximately 12.[89] It is a highly lipophilic compound (log P = 2.92).[2][254] At 37 °C (98.6 °F), or normal human body temperature, bicalutamide is practically insoluble in water (4.6 mg/L), acid (4.6 mg/L at pH 1), and alkali (3.7 mg/L at pH 8).[27][89] In organic solvents, it is slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and freely soluble in acetone and tetrahydrofuran.[27][89]

Bicalutamide is a synthetic and nonsteroidal compound which was derived from flutamide.[255] It is a bicyclic compound (has two rings) and can be classified as and has variously been referred to as an anilide (N-phenylamide) or aniline, a diarylpropionamide, and a toluidide.[255][247]

Analogues

See also: Discovery and development of antiandrogens

First-generation NSAAs including bicalutamide, flutamide, and nilutamide are all synthetic, nonsteroidal anilide derivatives and structural analogues of each other.[255] Bicalutamide is a diarylpropionamide while flutamide is a monoarylpropionamide and nilutamide is a hydantoin.[255] Bicalutamide and flutamide, though not nilutamide, can also be classified as toluidides.[247] All three of the compounds share a common 3-trifluoromethylaniline moiety.[256] Bicalutamide is a modification of flutamide in which a 4-fluorophenylsulfonyl moiety has been added and the nitro group on the original phenyl ring has been replaced with a cyano group.[257] Topilutamide, also known as fluridil, is another NSAA that is closely related structurally to the first-generation NSAAs, but, in contrast to them, is not used in the treatment of prostate cancer and is instead used exclusively as a topical antiandrogen in the treatment of pattern hair loss.[258][259][260]

Chemical structures of first-generation NSAAs

The second-generation NSAAs enzalutamide and apalutamide were derived from and are analogues of the first-generation NSAAs,[167][261] while another second-generation NSAA, darolutamide, is said to be structurally distinct and chemically unrelated to the other NSAAs.[262] Enzalutamide is a modification of bicalutamide in which the inter-ring linking chain has been altered and cyclized into a 5,5-dimethyl-4-oxo-2-thioxo imidazolidine moiety. In apalutamide, the 5,5-dimethyl groups of the imidazolidine ring of enzalutamide are cyclized to form an accessory cyclobutane ring and one of its phenyl rings is replaced with a pyridine ring.

Chemical structures of second-generation NSAAs

The first nonsteroidal androgens, the arylpropionamides, were discovered via structural modification of bicalutamide.[263] Unlike bicalutamide (which is purely antiandrogenic), these compounds show tissue-selective androgenic effects and were classified as selective androgen receptor modulators (SARMs).[263] Lead SARMs of this series included acetothiolutamide, enobosarm (ostarine; S-22), and andarine (acetamidoxolutamide or androxolutamide; S-4).[255][263][264] They are very close to bicalutamide structurally, with the key differences being that the linker sulfone of bicalutamide has been replaced with an ether or thioether group to confer agonism of the AR and the 4-fluoro atom of the pertinent phenyl ring has been substituted with an acetamido or cyano group to eliminate reactivity at the position.[265]

Chemical structures of arylpropionamide SARMs

A few radiolabeled derivatives of bicalutamide have been developed for potential use as radiotracers in medical imaging.[266][267] They include [18F]bicalutamide, 4-[76Br]bromobicalutamide, and [76Br]bromo-thiobicalutamide.[266][267] The latter two were found to have substantially increased affinity for the AR relative to that of bicautamide.[266] However, none of these agents have been evaluated in humans.[266][267]

5N-Bicalutamide, or 5-azabicalutamide, is a minor structural modification of bicalutamide which acts as a reversible covalent antagonist of the AR and has approximately 150-fold higher affinity for the AR and about 20-fold greater functional inhibition of the AR relative to bicalutamide.[268][269] It is among the most potent AR antagonists to have been developed and is being researched for potential use in the treatment of antiandrogen-resistant prostate cancer.[268]

Synthesis

A number of chemical syntheses of bicalutamide have been published in the literature.[252][270][271][272][273] The procedure of the first published synthesis of bicalutamide can be seen below.[270]

Bicalutamide synthesis[270]
 
 
Where the starting material is 4-cyano-3-(trifluoromethyl)aniline (also known as 4-amino-2-(trifluoromethyl)benzonitrile), DMA is dimethylacetamide, and mCPBA is meta-chloroperoxybenzoic acid.

History

Bicalutamide as well as all of the other currently marketed NSAAs were derived from structural modification of flutamide, which itself was originally synthesized as a bacteriostatic agent in 1967 at Schering Plough Corporation and was subsequently and serendipitously found to possess antiandrogenic activity.[274][275][276] Bicalutamide was discovered by Tucker and colleagues at Imperial Chemical Industries (ICI) in the 1980s and was selected for development from a group of over 2,000 synthesized compounds.[277][176][278][252] It was first patented in 1982[279] and was first reported in the scientific literature in June 1987.[280]

Bicalutamide was first studied in a phase I clinical trial in 1987[107] and the results of the first phase II clinical trial in prostate cancer were published in 1990.[281] The pharmaceutical division of ICI was split out into an independent company called Zeneca in 1993, and in April and May 1995, Zeneca (now AstraZeneca, after merging with Astra AB in 1999) began pre-approval marketing of bicalutamide for the treatment of prostate cancer in the U.S..[282] It was first launched in the U.K. in May 1995,[283] and was subsequently approved by the U.S. FDA on 4 October 1995, for the treatment of prostate cancer at a dosage of 50 mg/day in combination with a GnRH analogue.[284][285]

Following its introduction for use in combination with a GnRH analogue, bicalutamide was developed as a monotherapy at a dosage of 150 mg/day for the treatment of prostate cancer, and was approved for this indication in Europe, Canada, and a number of other countries in the late 1990s and early 2000s.[13][172][286][287] This application of bicalutamide was also under review by the FDA in the U.S. in 2002,[288] but ultimately was not approved in this country.[84] In Japan, bicalutamide is licensed at a dosage of 80 mg/day alone or in combination with a GnRH analogue for prostate cancer.[48] The unique 80 mg dosage of bicalutamide used in Japan was selected for development in this country on the basis of observed pharmacokinetic differences with bicalutamide in Japanese men.[49]

Subsequent to negative findings of bicalutamide monotherapy for LPC in the EPC clinical programme, approval of bicalutamide for use specifically in the treatment of LPC was withdrawn in a number of countries[14] including the U.K. (in October or November 2003)[15] and several other European countries and Canada (in August 2003).[13][289][290] In addition, the U.S. and Canada explicitly recommended against the use of 150 mg/day bicalutamide for this indication.[16] The drug is effective for, remains approved for, and continues to be used in the treatment of LAPC and mPC, on the other hand.[13]

The patent protection of bicalutamide expired in the U.S. in March 2009 and the drug has subsequently been available as a generic,[291] at greatly reduced cost.[292]

Bicalutamide was the fourth antiandrogen (and the third NSAA) to be introduced for the treatment of prostate cancer, following the SAA CPA in 1973[293] and the NSAAs flutamide in 1983 (1989 in the U.S.)[252][294] and nilutamide in 1989 (1996 in the U.S.).[256][295][296] It has been followed by abiraterone acetate in 2011, enzalutamide in 2012, apalutamide in 2018, and darolutamide in 2019, and may also be followed by in-development drugs such as proxalutamide and seviteronel.[297]

Society and culture

Generic names

Bicalutamide is the generic name of the drug in English and French and its INN, USAN, USP,[298] BAN, DCF, AAN,[89] and JAN.[38][299][80][300] It is also referred to as bicalutamidum in Latin, bicalutamida in Spanish and Portuguese, bicalutamid in German, and bikalutamid in Russian and other Slavic languages.[38][80] The "bica-" prefix corresponds to the fact that bicalutamide is a bicyclic compound, while the "-lutamide" suffix is the standard suffix for NSAAs.[301][302] Bicalutamide is also known by its former developmental code name ICI-176,334.[299][80][38]

Brand names

Bicalutamide is marketed by AstraZeneca in oral tablet form under the brand names Casodex, Cosudex, Calutide, Calumid, and Kalumid in many countries.[38][80][303][304] It is also marketed under the brand names Bicadex, Bical, Bicalox, Bicamide, Bicatlon, Bicusan, Binabic, Bypro, Calutol, and Ormandyl among others in various countries.[38] The drug is sold under a large number of generic trade names such as Apo-Bicalutamide, Bicalutamide Accord, Bicalutamide Actavis, Bicalutamide Bluefish, Bicalutamide Kabi, Bicalutamide Sandoz, and Bicalutamide Teva as well.[38] A combination formulation of bicalutamide and goserelin is marketed by AstraZeneca in Australia and New Zealand under the brand name ZolaCos-CP.[81][86][87][88]

Cost and generics

Bicalutamide is off-patent and available as a generic.[291] Unlike bicalutamide, the newer NSAA enzalutamide is still on-patent, and for this reason, is considerably more expensive in comparison.[305]

The patent protection of all three of the first-generation NSAAs has expired and flutamide and bicalutamide are both available as low-cost generics.[306][307] Nilutamide, on the other hand, has always been a poor third competitor to flutamide and bicalutamide and, in relation to this fact, has not been developed as a generic and is only available as brand name Nilandron, at least in the U.S.[306][307]

Bicalutamide is considerably less costly than GnRH analogues, which, in spite of some having been off-patent many years, have been reported (in 2013) to typically cost US$10,000–$15,000 per year (or about US$1,000 per month) of treatment.[308][309]

Sales and usage

Sales of bicalutamide (as Casodex) worldwide peaked at US$1.3 billion in 2007,[310] and it has been described as a "billion-dollar-a-year" drug prior to losing its patent protection starting in 2007.[43][311][258] In 2014, despite the introduction of abiraterone acetate in 2011 and enzalutamide in 2012, bicalutamide was still the most commonly prescribed drug in the treatment of metastatic castration-resistant prostate cancer (mCRPC).[43] Moreover, in spite of being off-patent, bicalutamide was said to still generate a few hundred million dollars in sales per year for AstraZeneca.[43] Total worldwide sales of brand name Casodex were approximately US$13.4 billion as of the end of 2018.[312][313][40][314][315][310][316][317][318][319][320][excessive citations]

Worldwide sales (millions, USD) of Casodex, 1995–2018
Year Sales Year Sales Year Sales Year Sales Year Sales Year Sales Year Sales Year Sales
1995 ~$15m 1998 $245m 2001 $569m 2004 $1012m 2007* $1335m 2010 $579m 2013 $376m 2016 $247m
1996 $109m 1999 $340m 2002 $644m 2005 $1123m 2008 $1258m 2011 $550m 2014 $320m 2017 $215m
1997 $200m 2000 $433m 2003 $854m 2006 $1206m 2009 $844m 2012 $454m 2015 $267m 2018 $201m
Notes: First generic availability (*) was in 2007.[311] Total sales as of end 2018 were $13.4 billion. Sources:[312][313][40][314][315][310][316][317][318][319][320]

Between January 2007 and December 2009 (a period of three years), 1,232,143 prescriptions of bicalutamide were dispensed in the U.S., or about 400,000 prescriptions per year.[44] During that time, bicalutamide accounted for about 87.2% of the NSAA market, while flutamide accounted for 10.5% of it and nilutamide for 2.3% of it.[44] Approximately 96% of bicalutamide prescriptions were written for diagnosis codes that clearly indicated neoplasm.[44] About 1,200, or 0.1% of bicalutamide prescriptions were dispensed to pediatric patients (age 0–16).[44]

Regulation

Bicalutamide is a prescription drug.[83] It is not specifically a controlled substance in any country and therefore is not an illegal drug.[10] However, the manufacture, sale, distribution, and possession of prescription drugs are all still subject to legal regulation throughout the world.[321][322][323]

Research

Bicalutamide has been studied in combination with the 5α-reductase inhibitors finasteride and dutasteride in prostate cancer.[324][325][326][327][328][329][330] It has also been studied in combination with raloxifene, a selective estrogen receptor modulator (SERM), for the treatment of prostate cancer.[331][332] Bicalutamide has been tested for the treatment of AR-positive ER/PR-negative locally advanced and metastatic breast cancer in women in a phase II study for this indication.[333][334][335] Enzalutamide is also being investigated for this type of cancer.[336][337] Bicalutamide has also been studied in a phase II clinical trial for ovarian cancer in women.[338]

Bicalutamide has been studied in the treatment of benign prostatic hyperplasia (BPH) in a 24-week trial of 15 patients at a dosage of 50 mg/day.[339][340] Prostate volume decreased by 26% in patients taking bicalutamide and urinary irritative symptom scores significantly decreased.[339][340] Conversely, peak urine flow rates and urine pressure flow examinations were not significantly different between bicalutamide and placebo.[339][340] The decrease in prostate volume achieved with bicalutamide was comparable to that observed with the 5α-reductase inhibitor finasteride, which is approved for the treatment of BPH.[341][342] Breast tenderness (93%), gynecomastia (54%), and sexual dysfunction (60%) were all reported as side effects of bicalutamide at the dosage used in the study, although no treatment discontinuations due to adverse effects occurred and sexual functioning was maintained in 75% of patients.[340][107]

A phase III clinical trial of bicalutamide in combination with an ethinylestradiol-containing combined oral contraceptive for the treatment of severe hirsutism in women with PCOS was completed in Italy in 2017 under supervision of the Italian Agency for Drugs (AIFA).[57]

Antiandrogens have been suggested for treating COVID-19 in men and as of May 2020 high-dose bicalutamide is in a phase II clinical trial for this purpose.[343][344]

Veterinary use

Bicalutamide may be used to treat hyperandrogenism and associated benign prostatic hyperplasia secondary to hyperadrenocorticism (caused by excessive adrenal androgens) in male ferrets.[345][346][347] However, it has not been formally assessed in controlled studies for this purpose.[347][348]

See also

References

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August 23, 2023
bicalutamide, sold, under, brand, name, casodex, among, others, antiandrogen, medication, that, primarily, used, treat, prostate, cancer, typically, used, together, with, gonadotropin, releasing, hormone, gnrh, analogue, surgical, removal, testicles, treat, me. Bicalutamide sold under the brand name Casodex among others is an antiandrogen medication that is primarily used to treat prostate cancer 10 It is typically used together with a gonadotropin releasing hormone GnRH analogue or surgical removal of the testicles to treat metastatic prostate cancer mPC 11 10 12 To a lesser extent it is used at high doses for locally advanced prostate cancer LAPC as a monotherapy without castration 4 2 13 Bicalutamide was also previously used as monotherapy to treat localized prostate cancer LPC but authorization for this use was withdrawn following unfavorable trial findings 13 14 15 16 Besides prostate cancer bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women 17 18 as a puberty blocker and component of feminizing hormone therapy for transgender girls and women 19 to treat gonadotropin independent early puberty in boys 20 and to prevent overly long lasting erections in men 21 It is taken by mouth 10 BicalutamideClinical dataPronunciationBicalutamide ˌ b aɪ k e ˈ l uː t e m aɪ d 1 BY ke LOO te myde 1 Trade namesCasodex Calutex othersOther namesICI 176 334 ZD 176 334AHFS Drugs comMonographMedlinePlusa697047License dataUS DailyMed Bicalutamide US FDA BicalutamidePregnancycategoryAU DRoutes ofadministrationBy mouth 2 Drug classNonsteroidal antiandrogenATC codeL02BB03 WHO Legal statusLegal statusAU S4 Prescription only UK POM Prescription only US only In general Prescription only Pharmacokinetic dataBioavailabilityWell absorbed absolute bioavailability unknown 3 Protein bindingRacemate 96 1 2 R Isomer 99 6 2 Mainly to albumin 2 MetabolismLiver extensively 4 9 Hydroxylation CYP3A4 Glucuronidation UGT1A9 Metabolites Bicalutamide glucuronide Hydroxybicalutamide Hydroxybicalutamide gluc All inactive 4 2 5 6 Elimination half lifeSingle dose 5 8 days 7 Continuous 7 10 days 8 ExcretionFeces 43 4 Urine 34 4 IdentifiersIUPAC name RS N 4 cyano 3 trifluoromethyl phenyl 3 4 fluorophenyl sulfonyl 2 hydroxy 2 methylpropanamideCAS Number90357 06 5 Y 113299 40 4 R isomer 113299 38 0 S isomer PubChem CID2375IUPHAR BPS2863DrugBankDB01128 YChemSpider2284 YUNIIA0Z3NAU9DPKEGGC08160 YChEBICHEBI 91617 YChEMBLChEMBL409 YPDB ligand198 PDBe RCSB PDB CompTox Dashboard EPA DTXSID2022678ECHA InfoCard100 126 100Chemical and physical dataFormulaC 18H 14F 4N 2O 4SMolar mass430 37 g mol 13D model JSmol Interactive imageChiralityRacemic mixture of R and S enantiomers Melting point191 to 193 C 376 to 379 F experimental Boiling point650 C 1 202 F predicted Solubility in water0 005SMILES CC O CS O O c1ccc F cc1 C O Nc1ccc C N c C F F F c1InChI InChI 1S C18H14F4N2O4S c1 17 26 10 29 27 28 14 6 3 12 19 4 7 14 16 25 24 13 5 2 11 9 23 15 8 13 18 20 21 22 h2 8 26H 10H2 1H3 H 24 25 YKey LKJPYSCBVHEWIU UHFFFAOYSA N Y verify Common side effects of bicalutamide in men include breast growth breast tenderness and hot flashes 10 Other side effects in men include feminization and sexual dysfunction 22 23 Some side effects like breast changes and feminization are minimal when combined with castration 24 While the medication appears to produce few side effects in women its use in women is not explicitly approved by the Food and Drug Administration FDA at this time 25 10 Use during pregnancy may harm the baby 10 In men with early prostate cancer bicalutamide monotherapy has been found to increase the likelihood of death from causes other than prostate cancer 26 13 Bicalutamide produces abnormal liver changes necessitating discontinuation in around 1 of people 27 13 Rarely it has been associated with cases of serious liver damage 10 serious lung toxicity 3 and sensitivity to light 28 29 Although the risk of adverse liver changes is small monitoring of liver function is recommended during treatment 10 Bicalutamide is a member of the nonsteroidal antiandrogen NSAA group of medications 3 It works by selectively blocking the androgen receptor AR the biological target of the androgen sex hormones testosterone and dihydrotestosterone DHT 30 It does not lower androgen levels 3 The medication can have some estrogen like effects in men when used as a monotherapy due to increased estradiol levels 31 32 33 Bicalutamide is well absorbed and its absorption is not affected by food 2 The elimination half life of the medication is around one week 2 10 It shows peripheral selectivity in animals but crosses the blood brain barrier and affects both the body and brain in humans 2 34 Bicalutamide was patented in 1982 and approved for medical use in 1995 35 It is on the World Health Organization s List of Essential Medicines 36 Bicalutamide is available as a generic medication 37 The drug is sold in more than 80 countries including most developed countries 38 39 40 It was at one time the most widely used antiandrogen in the treatment of prostate cancer with millions of men with the disease having been prescribed it 23 41 42 43 44 Although bicalutamide is also used for other indications besides prostate cancer the vast majority of prescriptions appear to be for treatment of prostate cancer 44 Contents 1 Medical uses 1 1 Available forms 2 Contraindications 3 Side effects 3 1 Comparison 4 Overdose 5 Interactions 6 Pharmacology 6 1 Pharmacodynamics 6 1 1 Antiandrogenic activity 6 1 2 Other activities 6 2 Pharmacokinetics 7 Chemistry 7 1 Analogues 7 2 Synthesis 8 History 9 Society and culture 9 1 Generic names 9 2 Brand names 9 3 Cost and generics 9 4 Sales and usage 9 5 Regulation 10 Research 11 Veterinary use 12 See also 13 References 14 Further readingMedical uses EditMain article Medical uses of bicalutamide Bicalutamide is approved for and mainly used in the following indications 45 Metastatic prostate cancer mPC in men in combination with a gonadotropin releasing hormone GnRH analogue or surgical castration at 50 mg day 27 4 46 Locally advanced prostate cancer LAPC in men as a monotherapy at 150 mg day not approved for this use in the United States 4 2 13 47 In Japan bicalutamide is uniquely used at a dosage of 80 mg day both in combination with castration and as a monotherapy in the treatment of prostate cancer 48 49 Bicalutamide is also employed for the following off label non approved indications To reduce the effects of the testosterone flare at the initiation of GnRH agonist therapy in men 50 51 Androgen dependent skin and hair conditions such as acne seborrhea excessive hair growth and scalp hair loss in women as well as high testosterone levels due to polycystic ovary syndrome PCOS in women at 25 to 50 mg day generally in combination with a birth control pill 17 52 53 54 55 56 57 Feminizing hormone therapy for transgender women in combination with an estrogen usually at 50 mg day 19 58 59 60 61 62 63 Peripheral precocious puberty in boys at 12 5 to 100 mg day in combination with an aromatase inhibitor like anastrozole especially for familial male limited precocious puberty testotoxicosis 27 64 65 66 67 68 20 69 Overly long lasting erections in men at 50 mg per week to 50 mg every other day 70 71 72 73 3 7 21 The medication has been suggested for but has uncertain effectiveness in the following indication Hypersexuality and paraphilias particularly in combination with chemical castration 74 75 76 77 78 79 For more information on these uses see the medical uses of bicalutamide article Available forms Edit Bicalutamide is available for the treatment of prostate cancer in most developed countries 80 38 81 including over 80 countries worldwide 39 40 It is available in 50 mg 80 mg in Japan 48 and 150 mg tablets for oral administration 82 83 The drug is registered for use as a 150 mg day monotherapy for the treatment of LAPC in at least 55 countries 2 with the U S being a notable exception where it is registered only for use at a dosage of 50 mg day in combination with castration 84 No other formulations or routes of administration are available or used 82 All formulations of bicalutamide are specifically indicated for the treatment of prostate cancer alone or in combination with surgical or medication castration 4 Due to the low water solubility of bicalutamide bicalutamide in oral bicalutamide tablets is micronized to ensure small and consistent particle sizes and optimize oral bioavailability 85 2 A combined formulation of bicalutamide and the GnRH agonist goserelin in which goserelin is provided as a subcutaneous implant for injection and bicalutamide is included as 50 mg tablets for oral ingestion is marketed in Australia and New Zealand under the brand name ZolaCos CP Zoladex Cosudex Combination Pack 81 86 87 88 Contraindications EditBicalutamide is pregnancy category X or contraindicated in pregnancy in the U S 27 and pregnancy category D the second most restricted rating in Australia 89 As such it is contraindicated in women during pregnancy and women who are sexually active and who can or may become pregnant are strongly recommended to take bicalutamide only in combination with adequate contraception 90 91 It is unknown whether bicalutamide is excreted in breast milk but many drugs are excreted in breast milk and for this reason bicalutamide treatment is similarly not recommended while breastfeeding 3 27 In individuals with severe though not mild to moderate hepatic impairment there is evidence that the elimination of bicalutamide is slowed and hence caution may be warranted in these patients as circulating levels of bicalutamide may be increased 2 92 In severe hepatic impairment the elimination half life of the active R enantiomer of bicalutamide is increased by about 1 75 fold 76 increase elimination half life of 5 9 and 10 4 days for normal and impaired patients respectively 13 93 94 The elimination half life of bicalutamide is unchanged in renal impairment 84 Side effects EditMain article Side effects of bicalutamide vte Major side effects of bicalutamide 95 96 97 98 99 100 101 Frequency Class of effect EffectVery common 10 Reproductive system and breast disorders Breast tenderness a Gynecomastia a Common 1 10 General and psychiatric disorders Asthenia Decreased libido Erectile dysfunction Hot flashesSkin and subcutaneoustissue disorders Decreased body hairHepato biliary disorders Elevated liver enzymes b Uncommon 0 1 1 Immune system disorders and hypersensitivity reactions Angioedema HivesRare lt 0 1 or unknown Respiratory disorders Lung disease c Skin and subcutaneous tissue disorders Sensitivity to lightHepato biliary disorders Liver toxicity c a b May occur as often as 90 of those taking bicalutamide but is mild to moderate in 90 of occurrences Incidence greatly decreased in combination with castration Usually transient rarely severe Resolves or improves with continued therapy or on discontinuation a b Reported in single cases but not observed in any large randomized trial With regular liver monitoring and discontinuation as needed The side effect profile of bicalutamide is highly dependent on sex that is on whether the person is male or female In men due to androgen deprivation a variety of side effects of varying severity may occur during bicalutamide treatment with breast pain tenderness and gynecomastia breast development enlargement being the most common 102 103 Gynecomastia occurs in up to 80 of men treated with bicalutamide monotherapy and is of mild to moderate severity in more than 90 of affected men 103 104 In addition to breast changes physical feminization and demasculinization in general including reduced body hair growth decreased muscle mass and strength feminine changes in fat mass and distribution reduced penile length and decreased semen ejaculate volume may occur in men 102 105 22 106 Other side effects that have been observed in men and that are similarly related to androgen deprivation include hot flashes sexual dysfunction e g loss of libido erectile dysfunction depression fatigue weakness and anemia 102 107 108 However most men have preserved sexual function with bicalutamide monotherapy 109 110 In females due to the minimal biological importance of androgens in this sex 111 112 the side effects of pure antiandrogens or NSAAs are few and bicalutamide has been found to be very well tolerated 25 However bicalutamide has been found to increase levels of total and LDL cholesterol in women 113 114 57 The non pharmacological side effect profile of bicalutamide i e side effects not related to its antiandrogenic activity is said to be similar to that with placebo 115 In any case general side effects of bicalutamide that might occur in either sex include diarrhea constipation abdominal pain nausea dry skin itching and rash 107 3 116 117 118 119 The drug is well tolerated at higher dosages than 50 mg day up to 600 mg day with rare additional side effects 84 120 121 Bicalutamide has been associated with abnormal liver function tests such as elevated liver enzymes 107 13 In the Early Prostate Cancer EPC clinical programme of bicalutamide for LPC and LAPC the rate of abnormal liver function tests with bicalutamide monotherapy was 3 4 relative to 1 9 for placebo 13 122 However higher rates up to 11 have been seen in other studies 18 27 Hepatic changes that have necessitated discontinuation of bicalutamide such as marked increases in liver enzymes or hepatitis have occurred in 0 3 to 1 5 of men in clinical trials or approximately 1 overall 27 13 33 122 123 Elevated liver enzymes with bicalutamide usually occur within the first 3 to 6 months of treatment 107 27 Monitoring of liver function during treatment is recommended particularly in the first few months 13 102 In men with early prostate cancer bicalutamide monotherapy has been found to increase non prostate cancer mortality 26 124 13 The reasons for the increase in mortality with bicalutamide in these men are unknown but possible factors could include androgen deprivation or drug related toxicity of bicalutamide 125 126 There are 10 published case reports of liver toxicity associated with bicalutamide as of 2022 127 128 129 130 Death occurred in 2 of these cases 127 131 132 Hundreds of additional cases of liver complications in people taking bicalutamide exist in the FDA Adverse Event Reporting System FAERS database 133 In all of the published case reports of liver toxicity with bicalutamide the onset of symptoms was within the first 6 months of treatment 128 129 130 Symptoms that may indicate liver dysfunction include nausea vomiting abdominal pain fatigue anorexia flu like symptoms dark urine and jaundice 27 There are also published case reports of interstitial pneumonitis and eosinophilic lung disease associated with bicalutamide 134 135 136 along with hundreds of additional instances in the FAERS database as well 133 Interstitial pneumonitis can potentially progress to pulmonary fibrosis and may be fatal Symptoms that may indicate lung dysfunction include dyspnea difficult breathing or shortness of breath cough and pharyngitis inflammation of the pharynx resulting in sore throat 137 The exact incidence of liver toxicity and interstitial pneumonitis with bicalutamide are unknown but both are said to be very rare events 129 138 139 A few cases of photosensitivity have been reported with bicalutamide 28 Hypersensitivity reactions drug allergy like angioedema and hives have also uncommonly been reported in association with bicalutamide 27 Because it is an antiandrogen bicalutamide has a theoretical risk of birth defects like ambiguous genitalia in male fetuses 90 91 140 141 Due to its teratogenic capacity contraception should be used in women taking bicalutamide who are fertile and sexually active 142 Comparison Edit See also Comparison of bicalutamide with other antiandrogens The side effect profile of bicalutamide in men and women differs from that of other antiandrogens and is considered favorable in comparison 143 110 144 145 Relative to GnRH analogues and the steroidal antiandrogen SAA cyproterone acetate CPA bicalutamide monotherapy has a much lower incidence and severity of hot flashes and sexual dysfunction 109 110 104 146 In addition unlike GnRH analogues and CPA bicalutamide monotherapy is not associated with decreased bone mineral density or osteoporosis 104 110 Conversely bicalutamide monotherapy is associated with much higher rates of breast tenderness gynecomastia and feminization in men than GnRH analogues and CPA 104 However gynecomastia with bicalutamide is rarely severe and discontinuation rates due to this side effect are fairly low 104 110 These differences in side effects between bicalutamide monotherapy GnRH analogues and CPA are attributed to the fact that whereas GnRH analogues and CPA suppress estrogen production bicalutamide monotherapy does not lower estrogen levels and in fact actually increases them 104 Bicalutamide does not share the risk of neuropsychiatric side effects like fatigue as well as cardiovascular side effects like coagulation changes blood clots fluid retention ischemic cardiomyopathy and adverse serum lipid changes that CPA has been associated with 146 147 148 149 It has a much lower risk of hepatotoxicity than flutamide and CPA and of interstitial pneumonitis than nilutamide 150 110 131 151 152 153 The drug also does not share the unique risks of diarrhea with flutamide and nausea vomiting visual disturbances and alcohol intolerance with nilutamide 110 146 151 Unlike enzalutamide bicalutamide is not associated with seizures or related central side effects like anxiety and insomnia 154 155 However although the risk of adverse liver changes with bicalutamide is low enzalutamide differs from bicalutamide in having no known risk of elevated liver enzymes or hepatotoxicity 156 157 In contrast to the SAA spironolactone bicalutamide does not have antimineralocorticoid effects 158 and hence is not associated with hyperkalemia urinary frequency dehydration hypotension or other related side effects 159 160 161 146 In women unlike CPA and spironolactone bicalutamide does not produce menstrual irregularity or amenorrhea and does not interfere with ovulation or fertility 52 162 Overdose EditA single oral dose of bicalutamide in humans that results in symptoms of overdose or that is considered to be life threatening has not been established 27 163 Dosages of up to 600 mg day have been well tolerated in clinical trials 164 and it is notable that there is a saturation of absorption with bicalutamide such that circulating levels of its active R enantiomer do not further increase above a dosage of 300 mg day 2 164 Overdose is considered unlikely to be life threatening with bicalutamide or other first generation NSAAs i e flutamide and nilutamide 165 A massive overdose of nilutamide 13 grams or 43 times the normal maximum 300 mg day clinical dosage in a 79 year old man was uneventful producing no clinical signs symptoms or toxicity 166 There is no specific antidote for bicalutamide or NSAA overdose and treatment should be based on symptoms if any are present 27 163 Interactions EditBicalutamide is almost exclusively metabolized by CYP3A4 4 As such its levels in the body may be altered by inhibitors and inducers of CYP3A4 7 For a list of CYP3A4 inhibitors and inducers see here However in spite of the fact bicalutamide is metabolized by CYP3A4 there is no evidence of clinically significant drug interactions when bicalutamide at a dosage of 150 mg day or less is co administered with drugs that inhibit or induce cytochrome P450 enzyme activity 13 In vitro studies suggest that bicalutamide may be able to inhibit CYP3A4 and to a lesser extent CYP2C9 CYP2C19 and CYP2D6 2 Conversely animal studies suggest that bicalutamide may induce cytochrome P450 enzymes 2 In a clinical study bicalutamide co administered with the CYP3A4 substrate midazolam caused only a small and statistically non significant increase in midazolam levels 27 presumably due to CYP3A4 inhibition 2 However this was well below increases in midazolam exposure with potent CYP3A4 inhibitors like ketoconazole 1500 itraconazole 1000 and erythromycin 350 and is considered to not be clinically important 2 There is no indication of clinically significant enzyme inhibition or induction with bicalutamide at doses of 150 mg day or below 2 Because bicalutamide circulates at relatively high concentrations and is highly protein bound it has the potential to displace other highly protein bound drugs like warfarin phenytoin theophylline and aspirin from plasma binding proteins 103 107 This could in turn result in increased free concentrations of such drugs and increased effects and or side effects potentially necessitating dosage adjustments 103 Bicalutamide has specifically been found to displace coumarin anticoagulants like warfarin from their plasma binding proteins namely albumin in vitro potentially resulting in an increased anticoagulant effect and for this reason close monitoring of prothrombin time and dosage adjustment as necessary is recommended when bicalutamide is used in combination with these drugs 167 168 169 However in spite of this no conclusive evidence of an interaction between bicalutamide and other drugs was found in clinical trials of nearly 3 000 patients 107 Pharmacology EditPharmacodynamics Edit Main article Pharmacology of bicalutamide Pharmacodynamics Antiandrogenic activity Edit Bicalutamide acts as a highly selective competitive silent antagonist of the AR IC50 159 243 nM the major biological target of the androgen sex hormones testosterone and DHT and hence is an antiandrogen 30 170 171 172 The activity of bicalutamide lies in the R isomer 173 Due to its selectivity for the AR bicalutamide does not interact importantly with other steroid hormone receptors and hence has no clinically relevant off target hormonal activity e g progestogenic estrogenic glucocorticoid antimineralocorticoid 174 34 173 45 However it has been reported that bicalutamide has weak affinity for the progesterone receptor PR where it is an antagonist and hence it could have some antiprogestogenic activity 175 Bicalutamide does not inhibit 5a reductase nor is known to inhibit other enzymes involved in androgen steroidogenesis e g CYP17A1 176 Although it does not bind to the estrogen receptors ERs bicalutamide can increase estrogen levels secondarily to AR blockade when used as a monotherapy in males and hence can have some indirect estrogenic effects in males 177 Bicalutamide neither suppresses nor inhibits androgen production in the body i e it does not act as an antigonadotropin or androgen steroidogenesis inhibitor or lower androgen levels and hence exclusively mediates its antiandrogenic effects by antagonizing the AR 3 174 173 In addition to the classical nuclear AR bicalutamide has been assessed at the membrane androgen receptors mARs and found to act as a potent antagonist of ZIP9 IC50 66 3 nM whereas it does not appear to interact with GPRC6A 178 179 The affinity of bicalutamide for the AR is relatively low as it is approximately 30 to 100 times lower than that of DHT which is 2 5 to 10 fold as potent as an AR agonist as testosterone in bioassays and is the main endogenous ligand of the receptor in the prostate gland 180 172 2 181 However typical clinical dosages of bicalutamide result in circulating levels of the drug that are thousands of times higher than those of testosterone and DHT allowing it to powerfully prevent them from binding to and activating the receptor 182 183 34 184 27 89 185 13 186 This is especially true in the case of surgical or medical castration in which testosterone levels in the circulation are approximately 95 reduced and DHT levels in the prostate gland are about 50 to 60 reduced 172 187 In women levels of testosterone are substantially lower 20 to 40 fold than in men 188 so much smaller doses of bicalutamide e g 25 mg day in the hirsutism studies are necessary 17 52 189 33 Blockade of the AR by bicalutamide in the pituitary gland and hypothalamus results in prevention of the negative feedback of androgens on the hypothalamic pituitary gonadal axis HPG axis in males and consequent disinhibition of pituitary luteinizing hormone LH secretion 109 This in turn results in an increase in circulating LH levels and activation of the gonadal production of testosterone and by extension production of estradiol 190 Levels of testosterone have been found to increase 1 5 to 2 fold 59 97 increase and levels of estradiol about 1 5 to 2 5 fold 65 146 increase in men treated with 150 mg day bicalutamide monotherapy 31 32 33 In addition to testosterone and estradiol there are smaller increases in concentrations of DHT sex hormone binding globulin and prolactin 33 Estradiol levels with bicalutamide monotherapy are similar to those in the low normal premenopausal female range while testosterone levels generally remain in the high end of the normal male range 32 191 174 Testosterone concentrations do not typically exceed the normal male range due to negative feedback on the HPG axis by the increased concentrations of estradiol 109 Bicalutamide influences the HPG axis and increases hormone levels only in men and not also in women 192 193 194 This is due to the much lower levels of androgens in women and their lack of basal suppression of the HPG axis in this sex 192 193 194 As evidenced by its effectiveness in the treatment of prostate cancer and other androgen dependent conditions the antiandrogenic actions of bicalutamide considerably exceed any impact of the increased levels of testosterone it results in 84 However the elevated levels of estradiol remain unopposed by bicalutamide and are responsible for the gynecomastia and feminizing side effects it causes in men 195 Although bicalutamide monotherapy increases gonadotropin and sex hormone levels in men this will not occur if bicalutamide is combined with an antigonadotropin such as a GnRH analogue estrogen or progestogen as these medications maintain negative feedback on the HPG axis 50 196 197 NSAA monotherapy including with bicalutamide shows a number of tolerability differences from methods of androgen deprivation therapy that incorporate surgical or medical castration For example the rates of hot flashes depression fatigue and sexual dysfunction are all much higher with GnRH analogues than with NSAA monotherapy It is thought that this is because GnRH analogues suppress estrogen production in addition to androgen production resulting in estrogen deficiency 198 199 200 In contrast NSAA monotherapy does not decrease estrogen levels and in fact increases them resulting in an excess of estrogens that compensates for androgen deficiency and allows for a preservation of mood energy and sexual function 198 199 200 Neurosteroids that are produced from testosterone like 3a androstanediol and 3b androstanediol which are ERb agonists and the former a potent GABAA receptor positive allosteric modulator may also be involved 201 202 203 204 205 206 207 In the specific case of sexual dysfunction an additional possibility for the difference is that without concomitant suppression of androgen production blockade of the AR by the bicalutamide in the brain is incomplete and insufficient to markedly influence sexual function citation needed Under normal circumstances bicalutamide has no capacity to activate the AR 208 209 However in prostate cancer mutations and overexpression of the AR can accumulate in prostate gland cells which can convert bicalutamide from an antagonist of the AR into an agonist 208 210 This can result in paradoxical stimulation of prostate cancer growth with bicalutamide and is responsible for the phenomenon of the antiandrogen withdrawal syndrome where antiandrogen discontinuation paradoxically slows the rate of prostate cancer growth 208 210 In transgender women breast development is a desired effect of antiandrogen or estrogen treatment 63 211 Breast development and gynecomastia induced by bicalutamide is thought to be mediated by increased activation of the ER secondary to blockade of the AR resulting in disinhibition of the ER in breast tissue and increased levels of estradiol 20 212 213 In addition to fat deposition connective tissue growth and ductal development bicalutamide has been found to produce moderate lobuloalveolar development of the breasts 214 215 216 However full lobuloalveolar maturation necessary for lactation and breastfeeding will not occur without progestogen treatment 214 215 216 Bicalutamide monotherapy seems to have minimal effect on testicular spermatogenesis testicular ultrastructure and certain aspects of male fertility 217 90 218 This seems to be because testosterone levels in the testes where 95 of testosterone in males is produced are extremely high up to 200 fold higher than circulating levels and only a small fraction less than 10 of the normal levels of testosterone in the testes are actually necessary to maintain spermatogenesis 219 220 221 As a result bicalutamide appears to not be able to compete with testosterone in this sole part of the body to an extent sufficient to considerably interfere with androgen signaling and function 219 220 221 However while bicalutamide does not seem to be able to adversely influence testicular spermatogenesis it may interfere with AR dependent sperm maturation and transport outside of the testes in the epididymides and vas deferens where androgen levels are far lower and hence may still be able to impair male fertility 222 In addition the combination of bicalutamide with other medications such as estrogens progestogens and GnRH analogues can compromise spermatogenesis due to their own adverse effects on male fertility 223 224 225 226 227 228 These medications are able to strongly suppress gonadal androgen production which can severely impair or abolish testicular spermatogenesis and estrogens also appear to have direct and potentially long lasting cytotoxic effects in the testes at sufficiently high concentrations 223 224 225 226 227 228 Other activities Edit Bicalutamide has been found to act as an inhibitor or inducer of certain cytochrome P450 enzymes including CYP3A4 CYP2C9 CYP2C19 and CYP2D6 in preclinical research but no evidence of this has been found in humans treated with up to 150 mg day 2 It has also been identified in vitro as a strong inhibitor of CYP27A1 cholesterol 27 hydroxylase and as an inhibitor of CYP46A1 cholesterol 24 hydroxylase but this has yet to be assessed or confirmed in vivo or in humans and the clinical significance remains unknown 229 230 Bicalutamide has been found to be a P glycoprotein ABCB1 inhibitor 231 232 233 Like other first generation NSAAs and enzalutamide it has been found to act as a weak non competitive inhibitor of GABAA receptor mediated currents in vitro IC50 5 2 mM 234 235 However unlike enzalutamide bicalutamide has not been found to be associated with seizures or other related adverse central effects so the clinical relevance of this finding is uncertain 234 235 Pharmacokinetics Edit Main article Pharmacology of bicalutamide Pharmacokinetics Though its absolute bioavailability in humans is unknown bicalutamide is known to be extensively and well absorbed 2 3 Its absorption is not affected by food 3 167 The absorption of bicalutamide is linear at doses up to 150 mg day and is saturable at doses above this with no further increases in steady state levels of bicalutamide occurring at doses above 300 mg day 2 13 236 164 Whereas absorption of R bicalutamide is slow with levels peaking at 31 to 39 hours after a dose S bicalutamide is much more rapidly absorbed 13 27 2 Steady state concentrations of the drug are reached after 4 to 12 weeks of treatment independently of dosage with a 10 to 20 fold progressive accumulation in levels of R bicalutamide 13 237 238 185 The long time to steady state levels is the result of bicalutamide s very long elimination half life 185 There is wide interindividual variability in R bicalutamide levels up to 16 fold with bicalutamide regardless of dosage 2 The tissue distribution of bicalutamide is not well characterized 239 The amount of bicalutamide in semen that could potentially be transferred to a female partner during sexual intercourse is low and is not thought to be important 89 Based on animal studies with rats and dogs it was thought that bicalutamide could not cross the blood brain barrier and hence could not enter the brain 240 34 241 242 As such it was initially thought to be a peripherally selective antiandrogen 240 34 However subsequent clinical studies found that this was not also the case for humans indicating species differences bicalutamide crosses into the human brain and in accordance produces effects and side effects consistent with central antiandrogenic action 2 109 243 244 245 In any case there is indication that bicalutamide might have at least some peripheral selectivity in humans 246 Bicalutamide is highly plasma protein bound 96 1 for racemic bicalutamide 99 6 for R bicalutamide and is bound mainly to albumin with negligible binding to SHBG and corticosteroid binding globulin 4 2 239 176 Bicalutamide is metabolized in the liver 4 167 R Bicalutamide is metabolized slowly and almost exclusively via hydroxylation by CYP3A4 into R hydroxybicalutamide 167 2 4 247 This metabolite is then glucuronidated by UGT1A9 167 2 9 6 In contrast to R bicalutamide S bicalutamide is metabolized rapidly and mainly by glucuronidation without hydroxylation 167 None of the metabolites of bicalutamide are known to be active and levels of the metabolites are low in plasma where unchanged biclautamide predominates 4 5 2 Due to the stereoselective metabolism of bicalutamide R bicalutamide has a far longer terminal half life than S bicalutamide and its levels are about 10 to 20 fold higher in comparison following a single dose and 100 fold higher at steady state 13 247 248 R Bicalutamide has a relatively long elimination half life of 5 8 days with a single dose and 7 to 10 days following repeated administration 8 Bicalutamide is eliminated in similar proportions in feces 43 and urine 34 while its metabolites are eliminated roughly equally in urine and bile 4 167 249 250 The drug is excreted to a substantial extent in unmetabolized form and both bicalutamide and its metabolites are eliminated mainly as glucuronide conjugates 173 The glucuronide conjugates of bicalutamide and its metabolites are eliminated from the circulation rapidly unlike unconjugated bicalutamide 2 167 251 The pharmacokinetics of bicalutamide are not affected by consumption of food a person s age or body weight renal impairment or mild to moderate hepatic impairment 2 185 However steady state levels of bicalutamide are higher in Japanese individuals than in white people 2 vte Bicalutamide metabolism in humans 2 9 Bicalutamide S Bicalutamide glucuronide R Hydroxybicalutamide R Hydroxybicalutamide glucuronide Glucuronidation via UGT1A9 Glucuronidation via UGT1A9 Hydroxylation via CYP3A4 This diagram illustrates the primary metabolic pathways involved in the metabolism of bicalutamide in humans Chemistry EditBicalutamide is a racemic mixture consisting of equal proportions of enantiomers R bicalutamide dextrorotatory and S bicalutamide levorotatory 27 Its systematic name IUPAC is RS N 4 cyano 3 trifluoromethyl phenyl 3 4 fluorophenyl sulfonyl 2 hydroxy 2 methylpropanamide 252 253 The compound has a chemical formula of C18H14F4N2O4S a molecular weight of 430 373 g mol and is a fine white to off white powder 27 89 The acid dissociation constant pKa of bicalutamide is approximately 12 89 It is a highly lipophilic compound log P 2 92 2 254 At 37 C 98 6 F or normal human body temperature bicalutamide is practically insoluble in water 4 6 mg L acid 4 6 mg L at pH 1 and alkali 3 7 mg L at pH 8 27 89 In organic solvents it is slightly soluble in chloroform and absolute ethanol sparingly soluble in methanol and freely soluble in acetone and tetrahydrofuran 27 89 Bicalutamide is a synthetic and nonsteroidal compound which was derived from flutamide 255 It is a bicyclic compound has two rings and can be classified as and has variously been referred to as an anilide N phenylamide or aniline a diarylpropionamide and a toluidide 255 247 Analogues Edit See also Discovery and development of antiandrogens First generation NSAAs including bicalutamide flutamide and nilutamide are all synthetic nonsteroidal anilide derivatives and structural analogues of each other 255 Bicalutamide is a diarylpropionamide while flutamide is a monoarylpropionamide and nilutamide is a hydantoin 255 Bicalutamide and flutamide though not nilutamide can also be classified as toluidides 247 All three of the compounds share a common 3 trifluoromethylaniline moiety 256 Bicalutamide is a modification of flutamide in which a 4 fluorophenylsulfonyl moiety has been added and the nitro group on the original phenyl ring has been replaced with a cyano group 257 Topilutamide also known as fluridil is another NSAA that is closely related structurally to the first generation NSAAs but in contrast to them is not used in the treatment of prostate cancer and is instead used exclusively as a topical antiandrogen in the treatment of pattern hair loss 258 259 260 Chemical structures of first generation NSAAs Flutamide Nilutamide Bicalutamide Topilutamide The second generation NSAAs enzalutamide and apalutamide were derived from and are analogues of the first generation NSAAs 167 261 while another second generation NSAA darolutamide is said to be structurally distinct and chemically unrelated to the other NSAAs 262 Enzalutamide is a modification of bicalutamide in which the inter ring linking chain has been altered and cyclized into a 5 5 dimethyl 4 oxo 2 thioxo imidazolidine moiety In apalutamide the 5 5 dimethyl groups of the imidazolidine ring of enzalutamide are cyclized to form an accessory cyclobutane ring and one of its phenyl rings is replaced with a pyridine ring Chemical structures of second generation NSAAs Enzalutamide Apalutamide Proxalutamide Darolutamide The first nonsteroidal androgens the arylpropionamides were discovered via structural modification of bicalutamide 263 Unlike bicalutamide which is purely antiandrogenic these compounds show tissue selective androgenic effects and were classified as selective androgen receptor modulators SARMs 263 Lead SARMs of this series included acetothiolutamide enobosarm ostarine S 22 and andarine acetamidoxolutamide or androxolutamide S 4 255 263 264 They are very close to bicalutamide structurally with the key differences being that the linker sulfone of bicalutamide has been replaced with an ether or thioether group to confer agonism of the AR and the 4 fluoro atom of the pertinent phenyl ring has been substituted with an acetamido or cyano group to eliminate reactivity at the position 265 Chemical structures of arylpropionamide SARMs Acetothiolutamide Enobosarm Andarine A few radiolabeled derivatives of bicalutamide have been developed for potential use as radiotracers in medical imaging 266 267 They include 18F bicalutamide 4 76Br bromobicalutamide and 76Br bromo thiobicalutamide 266 267 The latter two were found to have substantially increased affinity for the AR relative to that of bicautamide 266 However none of these agents have been evaluated in humans 266 267 5N Bicalutamide or 5 azabicalutamide is a minor structural modification of bicalutamide which acts as a reversible covalent antagonist of the AR and has approximately 150 fold higher affinity for the AR and about 20 fold greater functional inhibition of the AR relative to bicalutamide 268 269 It is among the most potent AR antagonists to have been developed and is being researched for potential use in the treatment of antiandrogen resistant prostate cancer 268 Synthesis Edit A number of chemical syntheses of bicalutamide have been published in the literature 252 270 271 272 273 The procedure of the first published synthesis of bicalutamide can be seen below 270 Bicalutamide synthesis 270 Where the starting material is 4 cyano 3 trifluoromethyl aniline also known as 4 amino 2 trifluoromethyl benzonitrile DMA is dimethylacetamide and mCPBA is meta chloroperoxybenzoic acid History EditBicalutamide as well as all of the other currently marketed NSAAs were derived from structural modification of flutamide which itself was originally synthesized as a bacteriostatic agent in 1967 at Schering Plough Corporation and was subsequently and serendipitously found to possess antiandrogenic activity 274 275 276 Bicalutamide was discovered by Tucker and colleagues at Imperial Chemical Industries ICI in the 1980s and was selected for development from a group of over 2 000 synthesized compounds 277 176 278 252 It was first patented in 1982 279 and was first reported in the scientific literature in June 1987 280 Bicalutamide was first studied in a phase I clinical trial in 1987 107 and the results of the first phase II clinical trial in prostate cancer were published in 1990 281 The pharmaceutical division of ICI was split out into an independent company called Zeneca in 1993 and in April and May 1995 Zeneca now AstraZeneca after merging with Astra AB in 1999 began pre approval marketing of bicalutamide for the treatment of prostate cancer in the U S 282 It was first launched in the U K in May 1995 283 and was subsequently approved by the U S FDA on 4 October 1995 for the treatment of prostate cancer at a dosage of 50 mg day in combination with a GnRH analogue 284 285 Following its introduction for use in combination with a GnRH analogue bicalutamide was developed as a monotherapy at a dosage of 150 mg day for the treatment of prostate cancer and was approved for this indication in Europe Canada and a number of other countries in the late 1990s and early 2000s 13 172 286 287 This application of bicalutamide was also under review by the FDA in the U S in 2002 288 but ultimately was not approved in this country 84 In Japan bicalutamide is licensed at a dosage of 80 mg day alone or in combination with a GnRH analogue for prostate cancer 48 The unique 80 mg dosage of bicalutamide used in Japan was selected for development in this country on the basis of observed pharmacokinetic differences with bicalutamide in Japanese men 49 Subsequent to negative findings of bicalutamide monotherapy for LPC in the EPC clinical programme approval of bicalutamide for use specifically in the treatment of LPC was withdrawn in a number of countries 14 including the U K in October or November 2003 15 and several other European countries and Canada in August 2003 13 289 290 In addition the U S and Canada explicitly recommended against the use of 150 mg day bicalutamide for this indication 16 The drug is effective for remains approved for and continues to be used in the treatment of LAPC and mPC on the other hand 13 The patent protection of bicalutamide expired in the U S in March 2009 and the drug has subsequently been available as a generic 291 at greatly reduced cost 292 Bicalutamide was the fourth antiandrogen and the third NSAA to be introduced for the treatment of prostate cancer following the SAA CPA in 1973 293 and the NSAAs flutamide in 1983 1989 in the U S 252 294 and nilutamide in 1989 1996 in the U S 256 295 296 It has been followed by abiraterone acetate in 2011 enzalutamide in 2012 apalutamide in 2018 and darolutamide in 2019 and may also be followed by in development drugs such as proxalutamide and seviteronel 297 Society and culture EditGeneric names Edit Bicalutamide is the generic name of the drug in English and French and its INN USAN USP 298 BAN DCF AAN 89 and JAN 38 299 80 300 It is also referred to as bicalutamidum in Latin bicalutamida in Spanish and Portuguese bicalutamid in German and bikalutamid in Russian and other Slavic languages 38 80 The bica prefix corresponds to the fact that bicalutamide is a bicyclic compound while the lutamide suffix is the standard suffix for NSAAs 301 302 Bicalutamide is also known by its former developmental code name ICI 176 334 299 80 38 Brand names Edit Bicalutamide is marketed by AstraZeneca in oral tablet form under the brand names Casodex Cosudex Calutide Calumid and Kalumid in many countries 38 80 303 304 It is also marketed under the brand names Bicadex Bical Bicalox Bicamide Bicatlon Bicusan Binabic Bypro Calutol and Ormandyl among others in various countries 38 The drug is sold under a large number of generic trade names such as Apo Bicalutamide Bicalutamide Accord Bicalutamide Actavis Bicalutamide Bluefish Bicalutamide Kabi Bicalutamide Sandoz and Bicalutamide Teva as well 38 A combination formulation of bicalutamide and goserelin is marketed by AstraZeneca in Australia and New Zealand under the brand name ZolaCos CP 81 86 87 88 Cost and generics Edit Bicalutamide is off patent and available as a generic 291 Unlike bicalutamide the newer NSAA enzalutamide is still on patent and for this reason is considerably more expensive in comparison 305 The patent protection of all three of the first generation NSAAs has expired and flutamide and bicalutamide are both available as low cost generics 306 307 Nilutamide on the other hand has always been a poor third competitor to flutamide and bicalutamide and in relation to this fact has not been developed as a generic and is only available as brand name Nilandron at least in the U S 306 307 Bicalutamide is considerably less costly than GnRH analogues which in spite of some having been off patent many years have been reported in 2013 to typically cost US 10 000 15 000 per year or about US 1 000 per month of treatment 308 309 Sales and usage Edit Sales of bicalutamide as Casodex worldwide peaked at US 1 3 billion in 2007 310 and it has been described as a billion dollar a year drug prior to losing its patent protection starting in 2007 43 311 258 In 2014 despite the introduction of abiraterone acetate in 2011 and enzalutamide in 2012 bicalutamide was still the most commonly prescribed drug in the treatment of metastatic castration resistant prostate cancer mCRPC 43 Moreover in spite of being off patent bicalutamide was said to still generate a few hundred million dollars in sales per year for AstraZeneca 43 Total worldwide sales of brand name Casodex were approximately US 13 4 billion as of the end of 2018 312 313 40 314 315 310 316 317 318 319 320 excessive citations Worldwide sales millions USD of Casodex 1995 2018 Year Sales Year Sales Year Sales Year Sales Year Sales Year Sales Year Sales Year Sales1995 15m 1998 245m 2001 569m 2004 1012m 2007 1335m 2010 579m 2013 376m 2016 247m1996 109m 1999 340m 2002 644m 2005 1123m 2008 1258m 2011 550m 2014 320m 2017 215m1997 200m 2000 433m 2003 854m 2006 1206m 2009 844m 2012 454m 2015 267m 2018 201mNotes First generic availability was in 2007 311 Total sales as of end 2018 were 13 4 billion Sources 312 313 40 314 315 310 316 317 318 319 320 Between January 2007 and December 2009 a period of three years 1 232 143 prescriptions of bicalutamide were dispensed in the U S or about 400 000 prescriptions per year 44 During that time bicalutamide accounted for about 87 2 of the NSAA market while flutamide accounted for 10 5 of it and nilutamide for 2 3 of it 44 Approximately 96 of bicalutamide prescriptions were written for diagnosis codes that clearly indicated neoplasm 44 About 1 200 or 0 1 of bicalutamide prescriptions were dispensed to pediatric patients age 0 16 44 Regulation Edit Bicalutamide is a prescription drug 83 It is not specifically a controlled substance in any country and therefore is not an illegal drug 10 However the manufacture sale distribution and possession of prescription drugs are all still subject to legal regulation throughout the world 321 322 323 Research EditBicalutamide has been studied in combination with the 5a reductase inhibitors finasteride and dutasteride in prostate cancer 324 325 326 327 328 329 330 It has also been studied in combination with raloxifene a selective estrogen receptor modulator SERM for the treatment of prostate cancer 331 332 Bicalutamide has been tested for the treatment of AR positive ER PR negative locally advanced and metastatic breast cancer in women in a phase II study for this indication 333 334 335 Enzalutamide is also being investigated for this type of cancer 336 337 Bicalutamide has also been studied in a phase II clinical trial for ovarian cancer in women 338 Bicalutamide has been studied in the treatment of benign prostatic hyperplasia BPH in a 24 week trial of 15 patients at a dosage of 50 mg day 339 340 Prostate volume decreased by 26 in patients taking bicalutamide and urinary irritative symptom scores significantly decreased 339 340 Conversely peak urine flow rates and urine pressure flow examinations were not significantly different between bicalutamide and placebo 339 340 The decrease in prostate volume achieved with bicalutamide was comparable to that observed with the 5a reductase inhibitor finasteride which is approved for the treatment of BPH 341 342 Breast tenderness 93 gynecomastia 54 and sexual dysfunction 60 were all reported as side effects of bicalutamide at the dosage used in the study although no treatment discontinuations due to adverse effects occurred and sexual functioning was maintained in 75 of patients 340 107 A phase III clinical trial of bicalutamide in combination with an ethinylestradiol containing combined oral contraceptive for the treatment of severe hirsutism in women with PCOS was completed in Italy in 2017 under supervision of the Italian Agency for Drugs AIFA 57 Antiandrogens have been suggested for treating COVID 19 in men and as of May 2020 high dose bicalutamide is in a phase II clinical trial for this purpose 343 344 Veterinary use EditBicalutamide may be used to treat hyperandrogenism and associated benign prostatic hyperplasia secondary to hyperadrenocorticism caused by excessive adrenal androgens in male ferrets 345 346 347 However it has not been formally assessed in controlled studies for this purpose 347 348 See also EditComparison of bicalutamide with other antiandrogensReferences Edit a b Finkel R Clark MA Cubeddu LX 2009 Pharmacology Lippincott Williams amp Wilkins pp 481 ISBN 978 0 7817 7155 9 a b c d e f g h i j k l m n o p q r s t u v w x y z aa ab ac ad ae af ag ah ai Cockshott ID 2004 Bicalutamide clinical pharmacokinetics and metabolism Clinical Pharmacokinetics 43 13 855 878 doi 10 2165 00003088 200443130 00003 PMID 15509184 S2CID 29912565 a b c d e f g h i j Dart RC 2004 Medical Toxicology Lippincott Williams amp Wilkins pp 497 521 ISBN 978 0 7817 2845 4 Archived from the original on 11 May 2016 a b c d e f g h i j k l m n Lemke TL Williams DA 2008 Foye s Principles of Medicinal Chemistry Lippincott Williams amp Wilkins pp 121 1288 1290 ISBN 978 0 7817 6879 5 Archived from the original on 8 September 2017 a b Dole EJ Holdsworth MT 1997 Nilutamide an antiandrogen for the treatment of prostate cancer The Annals of Pharmacotherapy 31 1 65 75 doi 10 1177 106002809703100112 PMID 8997470 S2CID 20347526 page 67 Currently information is not available regarding the activity of the major urinary metabolites of bicalutamide bicalutamide glucuronide and hydroxybicalutamide glucuronide a b Schellhammer PF September 2002 An evaluation of bicalutamide in the treatment of prostate cancer Expert Opinion on Pharmacotherapy 3 9 1313 28 doi 10 1517 14656566 3 9 1313 PMID 12186624 S2CID 32216411 The clearance of bicalutamide occurs pre dominantly by hepatic metabolism and glucuronidation with excretion of the resulting inactive metabolites in the urine and faces a b c Skidmore Roth L 17 April 2013 Mosby s 2014 Nursing Drug Reference Elsevieron VitalSource Elsevier Health Sciences pp 193 194 ISBN 978 0 323 22267 9 a b Jordan VC Furr BJ 5 February 2010 Hormone Therapy in Breast and Prostate Cancer Springer Science amp Business Media pp 350 ISBN 978 1 59259 152 7 Archived from the original on 29 May 2016 a b c Grosse L Campeau AS Caron S Morin FA Meunier K Trottier J Caron P Verreault M Barbier O August 2013 Enantiomer selective glucuronidation of the non steroidal pure anti androgen bicalutamide by human liver and kidney role of the human UDP glucuronosyltransferase UGT 1A9 enzyme Basic amp Clinical Pharmacology amp Toxicology 113 2 92 102 doi 10 1111 bcpt 12071 PMC 3815647 PMID 23527766 a b c d e f g h i j Bicalutamide The American Society of Health System Pharmacists Archived from the original on 29 December 2016 Retrieved 8 December 2016 Wass JA Stewart PM 28 July 2011 Oxford Textbook of Endocrinology and Diabetes OUP Oxford pp 1625 ISBN 978 0 19 923529 2 Archived from the original on 11 May 2016 Shergill I Arya M Grange PR Mundy AR 2010 Medical Therapy in Urology Springer Science amp Business Media p 40 ISBN 9781848827042 Archived from the original on 28 October 2014 a b c d e f g h i j k l m n o p q r s t Wellington K Keam SJ 2006 Bicalutamide 150mg a review of its use in the treatment of locally advanced prostate cancer PDF Drugs 66 6 837 50 doi 10 2165 00003495 200666060 00007 PMID 16706554 S2CID 46966712 Archived from the original PDF on 28 August 2016 Retrieved 13 August 2016 a b Shahani R Fleshner NE Zlotta AR 2007 Pharmacotherapy for prostate cancer the role of hormonal treatment Discovery Medicine 7 39 118 24 PMID 18093474 a b Bowsher W Carter A 15 April 2008 Challenges in Prostate Cancer John Wiley amp Sons pp 146 ISBN 978 1 4051 7177 9 a b Nargund VH Raghavan D Sandler HM 17 January 2015 Urological Oncology Springer pp 823 ISBN 978 0 85729 482 1 On the other hand the 150 mg dose of bicalutamide has been associated with some safety concerns such as a higher death rate when added to active surveillance in the early prostate cancer trialists group study 29 which has led the United States and Canada to recommend against prescribing the 150 mg dose 30 a b c Williams H Bigby M Diepgen T Herxheimer A Naldi L Rzany B 22 January 2009 Evidence Based Dermatology John Wiley amp Sons pp 529 ISBN 978 1 4443 0017 8 Archived from the original on 2 May 2016 a b Carvalho RM Santos LD Ramos PM Machado CJ Acioly P Frattini SC Barcaui CB Donda AL Melo DF January 2022 Bicalutamide and the new perspectives for female pattern hair loss treatment What dermatologists should know J Cosmet Dermatol 21 10 4171 4175 doi 10 1111 jocd 14773 PMID 35032336 S2CID 253239337 a b Randolph JF December 2018 Gender Affirming Hormone Therapy for Transgender Females Clin Obstet Gynecol 61 4 705 721 doi 10 1097 GRF 0000000000000396 PMID 30256230 S2CID 52821192 a b c Jameson JL De Groot LJ 25 February 2015 Edndocrinology Adult and Pediatric Elsevier Health Sciences pp 2425 2426 2139 ISBN 978 0 323 32195 2 a b Yuan J Desouza R Westney OL Wang R 2008 Insights of priapism mechanism and rationale treatment for recurrent priapism Asian Journal of Andrology 10 1 88 101 doi 10 1111 j 1745 7262 2008 00314 x PMID 18087648 a b Elliott S Latini DM Walker LM Wassersug R Robinson JW 2010 Androgen deprivation therapy for prostate cancer recommendations to improve patient and partner quality of life The Journal of Sexual Medicine 7 9 2996 3010 doi 10 1111 j 1743 6109 2010 01902 x PMID 20626600 a b Hammerer P Manka L 2019 Androgen Deprivation Therapy for Advanced Prostate Cancer Urologic Oncology Springer International Publishing pp 255 276 doi 10 1007 978 3 319 42623 5 77 ISBN 978 3 319 42622 8 Bicalutamide is the most widely used antiandrogen in the treatment of prostate cancer Common side effects of bicalutamide include breast enlargement breast tenderness hot flashes and constipation as well as feminization and changes in mood and liver as well as lung toxicity monitoring of liver enzymes is recommended during treatment Schellhammer and Davis 2004 Droz J Audisio RA 2 October 2012 Management of Urological Cancers in Older People Springer Science amp Business Media pp 84 ISBN 978 0 85729 986 4 Archived from the original on 11 May 2016 a b Shapiro J 12 November 2012 Hair Disorders Current Concepts in Pathophysiology Diagnosis and Management An Issue of Dermatologic Clinics Elsevier Health Sciences pp 187 ISBN 978 1 4557 7169 1 a b Jia AY Spratt DE June 2022 Bicalutamide Monotherapy With Radiation Therapy for Localized Prostate Cancer A Non Evidence Based Alternative Int J Radiat Oncol Biol Phys 113 2 316 319 doi 10 1016 j ijrobp 2022 01 037 PMID 35569476 S2CID 248765294 Four other randomized trials using BICmono have also raised concerns about either lack of efficacy or even harm from this treatment approach compared with placebo or no hormone therapy SPCG 6 randomized 1218 patients to either 150 mg of BICmono daily or placebo In the subset of patients with LPCa managed with observation survival was significantly worse with BIC than placebo hazard ratio HR 1 47 95 confidence interval 1 06 2 03 10 Two other randomized trials were part of the early prostate cancer program 11 which conducted 3 randomized trials that were pooled together to determine the benefit of BICmono SPCG 6 was one of the 3 trials Overall in the combined 8113 patient pooled cohort after a median follow up of 7 years there was no improvement even in progression free survival from the use of adjuvant BIC in LPCa and there was a trend for worse overall survival HR 1 16 95 confidence interval 0 99 1 37 P 07 Although not in LPCa NRG RTOG 9601 demonstrated findings consistent with the prior trials 12 This trial randomized men to postprostatectomy salvage radiation therapy plus placebo versus 150 mg of BICmono daily for 2 years After a median follow up of 13 years the trial showed that there were significantly more grade 3 to 5 cardiac events in the BICmono arm In patients with less aggressive disease with lower PSAs prostate specific antigens more analogous to LPCa other cause mortality was significantly higher in the BICmono arm In patients with high PSAs gt 1 5 ng mL which with modern molecular positron emission tomography imaging would be expected to have high rates of regional and distant metastatic disease a survival benefit from the addition of BIC was observed This is consistent with results from the early prostate cancer studies that showed that only patients with more advanced disease derived benefit from BICmono 10 Thus all the randomized evidence from 5 trials Table 1 demonstrates that in LPCa BICmono had no clinically significant oncologic activity over placebo no treatment and consistent trends with long term use resulted in worse survival a b c d e f g h i j k l m n o p q r Casodex bicalutamide tablet DailyMed 1 September 2019 Retrieved 7 May 2020 a b Lee K Oda Y Sakaguchi M Yamamoto A Nishigori C May 2016 Drug induced photosensitivity to bicalutamide case report and review of the literature Photodermatology Photoimmunology amp Photomedicine 32 3 161 4 doi 10 1111 phpp 12230 PMID 26663090 S2CID 2761388 Lee K et al 2016 Drug induced photosensitivity to bicalutamide case report and review of the literature Reactions Weekly 1612 1 161 4 doi 10 1007 s40278 016 19790 1 PMID 26663090 a b Singh SM Gauthier S Labrie F February 2000 Androgen receptor antagonists antiandrogens structure activity relationships Current Medicinal Chemistry 7 2 211 47 doi 10 2174 0929867003375371 PMID 10637363 a b Strauss III JF Barbieri RL 28 August 2013 Yen amp Jaffe s Reproductive Endocrinology Physiology Pathophysiology and Clinical Management Elsevier Health Sciences pp 688 ISBN 978 1 4557 5972 9 Bone density improves in men receiving bicalutamide most likely secondary to the 146 increase in estradiol and the fact that estradiol is the major mediator of bone density in men a b c Marcus R Feldman D Nelson D Rosen CJ 8 November 2007 Osteoporosis Academic Press pp 1354 ISBN 978 0 08 055347 4 Archived from the original on 11 June 2016 a b c d e Mahler C Verhelst J Denis L May 1998 Clinical pharmacokinetics of the antiandrogens and their efficacy in prostate cancer Clinical Pharmacokinetics 34 5 405 17 doi 10 2165 00003088 199834050 00005 PMID 9592622 S2CID 25200595 a b c d e Furr BJ Tucker H January 1996 The preclinical development of bicalutamide pharmacodynamics and mechanism of action Urology 47 1A Suppl 13 25 discussion 29 32 doi 10 1016 S0090 4295 96 80003 3 PMID 8560673 Fischer J Ganellin CR 2006 Analogue based Drug Discovery John Wiley amp Sons p 515 ISBN 9783527607495 World Health Organization 2019 World Health Organization model list of essential medicines 21st list 2019 Geneva World Health Organization hdl 10665 325771 WHO MVP EMP IAU 2019 06 License CC BY NC SA 3 0 IGO Hamilton R 2015 Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab Coat Edition Jones amp Bartlett Learning p 381 ISBN 9781284057560 a b c d e f g h Bicalutamide International Drug Names Drugs com Archived from the original on 18 September 2016 Retrieved 13 August 2016 a b Akaza H 1999 A new anti androgen bicalutamide Casodex for the treatment of prostate cancer basic clinical aspects Gan to Kagaku Ryoho Cancer amp Chemotherapy in Japanese 26 8 1201 7 PMID 10431591 a b c d 1999 Annual Report and Form 20 F PDF AstraZeneca Retrieved 1 July 2017 Mukherji D Pezaro CJ De Bono JS February 2012 MDV3100 for the treatment of prostate cancer Expert Opinion on Investigational Drugs 21 2 227 33 doi 10 1517 13543784 2012 651125 PMID 22229405 S2CID 46339544 Pchejetski D Alshaker H Stebbing J 2014 Castrate resistant prostate cancer the future of antiandrogens PDF Trends in Urology amp Men s Health 5 1 7 10 doi 10 1002 tre 371 S2CID 57988002 a b c d Campbell T 22 January 2014 Slowing Sales for Johnson amp Johnson s Zytiga May Be Good News for Medivation The Motley Fool Archived from the original on 26 August 2016 Retrieved 20 July 2016 the most commonly prescribed treatment for metastatic castration resistant prostate cancer bicalutamide That was sold as AstraZeneca s billion dollar a year drug Casodex before losing patent protection in 2008 AstraZeneca still generates a few hundred million dollars in sales from Casodex a b c d e f Chang S 10 March 2010 Bicalutamide BPCA Drug Use Review in the Pediatric Population PDF U S Department of Health and Human Service archived PDF from the original on 24 October 2016 retrieved 20 July 2016 a b Bagatelle C Bremner WJ 27 May 2003 Androgens in Health and Disease Springer Science amp Business Media pp 25 ISBN 978 1 59259 388 0 Klotz L Schellhammer P March 2005 Combined androgen blockade the case for bicalutamide Clinical Prostate Cancer 3 4 215 9 doi 10 3816 cgc 2005 n 002 PMID 15882477 Schellhammer PF Sharifi R Block NL Soloway MS Venner PM Patterson AL Sarosdy MF Vogelzang NJ Schellenger JJ Kolvenbag GJ September 1997 Clinical benefits of bicalutamide compared with flutamide in combined androgen blockade for patients with advanced prostatic carcinoma final report of a double blind randomized multicenter trial Casodex Combination Study Group Urology 50 3 330 6 doi 10 1016 S0090 4295 97 00279 3 PMID 9301693 a b c Suzuki H Kamiya N Imamoto T Kawamura K Yano M Takano M Utsumi T Naya Y Ichikawa T October 2008 Current topics and perspectives relating to hormone therapy for prostate cancer International Journal of Clinical Oncology 13 5 401 10 doi 10 1007 s10147 008 0830 y PMID 18946750 S2CID 32859879 a b Usami M Akaza H Arai Y Hirano Y Kagawa S Kanetake H Naito S Sumiyoshi Y Takimoto Y Terai A Yoshida H Ohashi Y 2007 Bicalutamide 80 mg combined with a luteinizing hormone releasing hormone agonist LHRH A versus LHRH A monotherapy in advanced prostate cancer findings from a phase III randomized double blind multicenter trial in Japanese patients Prostate Cancer Prostatic Dis 10 2 194 201 doi 10 1038 sj pcan 4500934 PMID 17199134 In most countries bicalutamide is given at a dose of 50 mg when used in combination with an LHRH A However based on pharmacokinetic and pharmacodynamic data the approved dose of bicalutamide in Japanese men is 80 mg per day a b Melmed S 1 January 2016 Williams Textbook of Endocrinology Elsevier Health Sciences pp 752 ISBN 978 0 323 29738 7 GnRH analogues both agonists and antagonists severely suppress endogenous gonadotropin and testosterone production Administration of GnRH agonists e g leuprolide goserelin produces an initial stimulation of gonadotropin and testosterone secretion known as a flare which is followed in 1 to 2 weeks by GnRH receptor downregulation and marked suppression of gonadotropins and testosterone to castration levels To prevent the potential complications associated with the testosterone flare AR antagonists e g bicalutamide are usually coadministered with a GnRH agonist for men with metastatic prostate cancer 399 Sugiono M Winkler MH Okeke AA Benney M Gillatt DA 2005 Bicalutamide vs cyproterone acetate in preventing flare with LHRH analogue therapy for prostate cancer a pilot study Prostate Cancer and Prostatic Diseases 8 1 91 4 doi 10 1038 sj pcan 4500784 PMID 15711607 a b c Erem C 2013 Update on idiopathic hirsutism diagnosis and treatment Acta Clinica Belgica 68 4 268 74 doi 10 2143 ACB 3267 PMID 24455796 S2CID 39120534 Ascenso A Marques HC January 2009 Acne in the adult Mini Reviews in Medicinal Chemistry 9 1 1 10 doi 10 2174 138955709787001730 PMID 19149656 Kaur S Verma P Sangwan A Dayal S Jain VK 2016 Etiopathogenesis and Therapeutic Approach to Adult Onset Acne Indian Journal of Dermatology 61 4 403 7 doi 10 4103 0019 5154 185703 PMC 4966398 PMID 27512185 Lotti F Maggi M 2015 Hormonal Treatment for Skin Androgen Related Disorders European Handbook of Dermatological Treatments 1451 1464 doi 10 1007 978 3 662 45139 7 142 ISBN 978 3 662 45138 0 Muderris II Oner G 2009 Hirsutizm Tedavisinde Flutamid ve Bikalutamid Kullanimi Flutamide and Bicalutamide Treatment in Hirsutism Turkiye Klinikleri Journal of Endocrinology Special Topics in Turkish 2 2 110 2 ISSN 1304 0529 a b c Moretti C Guccione L Di Giacinto P Simonelli I Exacoustos C Toscano V Motta C De Leo V Petraglia F Lenzi A March 2018 Combined Oral Contraception and Bicalutamide 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Interventions to Improve Growth Handbook of Growth and Growth Monitoring in Health and Disease pp 1199 1212 doi 10 1007 978 1 4419 1795 9 71 ISBN 978 1 4419 1794 2 Zacharin M 2019 Disorders of Puberty Pharmacotherapeutic Strategies for Management Pediatric Pharmacotherapy Handbook of Experimental Pharmacology Vol 261 pp 507 538 doi 10 1007 164 2019 208 ISBN 978 3 030 50493 9 ISSN 0171 2004 PMID 31144045 S2CID 169040406 Kliegman RM Stanton B St Geme J Schor NF 17 April 2015 Nelson Textbook of Pediatrics Elsevier Health Sciences pp 2661 ISBN 978 0 323 26352 8 Reiter EO Mauras N McCormick K Kulshreshtha B Amrhein J De Luca F et al October 2010 Bicalutamide plus anastrozole for the treatment of gonadotropin independent precocious puberty in boys with testotoxicosis a phase II open label pilot study BATT Journal of Pediatric Endocrinology amp Metabolism 23 10 999 1009 doi 10 1515 jpem 2010 161 PMID 21158211 S2CID 110630 Levey HR Kutlu O Bivalacqua TJ January 2012 Medical management of 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effects of androgen deprivation treatment in sex offenders The Journal of the American Academy of Psychiatry and the Law 37 1 53 8 PMID 19297634 Khan O Mashru A 2016 The efficacy safety and ethics of the use of testosterone suppressing agents in the management of sex offending Current Opinion in Endocrinology Diabetes and Obesity 23 3 271 8 doi 10 1097 MED 0000000000000257 PMID 27032060 S2CID 43286710 Dangerous Sex Offenders A Task Force Report of the American Psychiatric Association American Psychiatric Pub 1999 pp 111 ISBN 978 0 89042 280 9 Houts FW Taller I Tucker DE Berlin FS 2011 Androgen deprivation treatment of sexual behavior Advances in Psychosomatic Medicine 31 149 63 doi 10 1159 000330196 ISBN 978 3 8055 9825 5 PMID 22005210 Rousseau L Couture M Dupont A Labrie F Couture N 1990 Effect of combined androgen blockade with an LHRH agonist and flutamide in one severe case of male exhibitionism The Canadian Journal of Psychiatry 35 4 338 41 doi 10 1177 070674379003500412 PMID 2189544 S2CID 28970865 a b c d e Swiss Pharmaceutical Society ed January 2000 Index Nominum 2000 International Drug Directory Taylor amp Francis pp 123 ISBN 978 3 88763 075 1 Archived from the original on 24 April 2016 a b c Sweetman SC 2011 Martindale The Complete Drug Reference Pharmaceutical Press pp 750 751 ISBN 978 0 85369 933 0 a b White R Bradnam V 11 March 2015 Handbook of Drug Administration via Enteral Feeding Tubes 3rd ed Pharmaceutical Press pp 133 ISBN 978 0 85711 162 3 a b Morton IK Hall J 2001 The Avery Complete Guide to Medicines Avery pp 105 106 ISBN 978 1 58333 105 7 a b c d e Chabner BA Longo DL 8 November 2010 Cancer Chemotherapy and Biotherapy Principles and Practice Lippincott Williams amp Wilkins pp 679 680 ISBN 978 1 60547 431 1 From a structural standpoint antiandrogens are classified as steroidal including cyproterone acetate Androcur and megestrol acetate or nonsteroidal including flutamide Eulexin others bicalutamide Casodex and nilutamide Nilandron The steroidal antiandrogens are rarely used Kolvenbag GJ Furr BJ Blackledge GR December 1998 Receptor affinity and potency of non steroidal antiandrogens translation of preclinical findings into clinical activity Prostate Cancer Prostatic Dis 1 6 307 314 doi 10 1038 sj pcan 4500262 PMID 12496872 S2CID 33497597 In addition since bicalutamide has a low solubility authentic Casodex is micronised to ensure a small and consistent particle size to optimise bioavailability a b Zolacos CP Drugs com Archived from the original on 20 September 2016 a b Zolacos CP PDF MIMS myDr April 2007 Archived from the original PDF on 17 September 2016 a b ZOLACOS CP PDF New Zealand Data Sheet 25 July 2016 Archived PDF from the original on 19 September 2016 a b c d e f g h COSUDEX bicalutamide 150 mg tablets TGA Archived from the original on 14 September 2016 a b c Iswaran TJ Imai M Betton GR Siddall RA May 1997 An overview of animal toxicology studies with bicalutamide ICI 176 334 The Journal of Toxicological Sciences 22 2 75 88 doi 10 2131 jts 22 2 75 PMID 9198005 a b Smith RE 4 April 2013 Medicinal Chemistry Fusion of Traditional and Western Medicine Bentham Science Publishers pp 306 ISBN 978 1 60805 149 6 Archived from the original on 29 May 2016 Skeel RT Khleif SN 2011 Handbook of Cancer Chemotherapy Lippincott Williams amp Wilkins pp 724 ISBN 9781608317820 Archived from the original on 29 May 2016 Mosby s GenRx A Comprehensive Reference for Generic and Brand Prescription Drugs Mosby 2001 pp 289 290 ISBN 978 0 323 00629 3 Duplay D 2004 Physicians Desk Reference Thomson PDR ISBN 978 1 56363 471 0 Mcleod DG September 2002 Emerging role of adjuvant hormonal therapy Urology 60 3 Suppl 1 13 20 discussion 21 doi 10 1016 S0090 4295 02 01562 5 PMID 12231039 Bicalutamide PDF Richmond Hill Ontario Nu Pharm Inc October 2009 Bennett CL Raisch DW Sartor O October 2002 Pneumonitis associated with nonsteroidal antiandrogens presumptive evidence of a class effect Annals of Internal Medicine 137 7 625 doi 10 7326 0003 4819 137 7 200210010 00029 PMID 12353966 An estimated 0 77 of the 6 480 nilutamide treated patients 0 04 of the 41 700 flutamide treated patients and 0 01 of the 86 800 bicalutamide treated patients developed pneumonitis during the study period Molina Mancero G Picon X Di Tullio F Ernst G Dezanzo P Salvado A Chertcoff JF October 2016 Neumonia intersticial inducida por bloqueo androgenico maximo como tratamiento de cancer de prostata avanzado Fatal interstitial lung disease associated with maximum androgen blockade Report of one case Revista medica de Chile in Spanish 144 10 1356 1359 doi 10 4067 S0034 98872016001000017 PMID 28074993 Lee K Oda Y Sakaguchi M Yamamoto A Nishigori C May 2016 Drug induced photosensitivity to bicalutamide case report and review of the literature Photodermatology Photoimmunology amp Photomedicine 32 3 161 164 doi 10 1111 phpp 12230 PMID 26663090 S2CID 2761388 Gretarsdottir HM Bjornsdottir E Bjornsson ES 2018 Bicalutamide Associated Acute Liver Injury and Migratory Arthralgia A Rare but Clinically Important Adverse Effect Case Reports in Gastroenterology 12 2 266 270 doi 10 1159 000485175 ISSN 1662 0631 S2CID 81661015 Anderson J March 2003 The role of antiandrogen monotherapy in the treatment of prostate cancer BJU International 91 5 455 461 doi 10 1046 j 1464 410X 2003 04026 x PMID 12603397 S2CID 8639102 a b c d Lehne RA 2013 Pharmacology for Nursing Care Elsevier Health Sciences pp 1297 ISBN 978 1 4377 3582 6 a b c d Wirth MP Hakenberg OW Froehner M February 2007 Antiandrogens in the treatment of prostate cancer European Urology 51 2 306 13 discussion 314 doi 10 1016 j eururo 2006 08 043 PMID 17007995 a b c d e f Wellington K Keam SJ 2006 Bicalutamide 150mg a review of its use in the treatment of locally advanced prostate cancer Drugs 66 6 837 50 doi 10 2165 00003495 200666060 00007 PMID 16706554 S2CID 46966712 Higano CS February 2003 Side effects of androgen deprivation therapy monitoring and minimizing toxicity 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Archived from the original on 10 June 2016 a b c d e Iversen P Melezinek I Schmidt A January 2001 Nonsteroidal antiandrogens a therapeutic option for patients with advanced prostate cancer who wish to retain sexual interest and function BJU International 87 1 47 56 doi 10 1046 j 1464 410x 2001 00988 x PMID 11121992 S2CID 28215804 a b c d e f g Anderson J March 2003 The role of antiandrogen monotherapy in the treatment of prostate cancer BJU Int 91 5 455 61 doi 10 1046 j 1464 410X 2003 04026 x PMID 12603397 S2CID 8639102 Kathryn Korkidakis A Reid RL 2017 Testosterone in Women Measurement and Therapeutic Use Journal of Obstetrics and Gynaecology Canada 39 3 124 130 doi 10 1016 j jogc 2017 01 006 PMID 28343552 Davis SR Wahlin Jacobsen S 2015 Testosterone in women the clinical significance The Lancet Diabetes amp Endocrinology 3 12 980 92 doi 10 1016 S2213 8587 15 00284 3 PMID 26358173 Cignarella A Mioni R Sabbadin C Dassie F Parolin M Vettor R Barbot M Scaroni C December 2020 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compounds Furthermore the recent data from the EPC programme suggest that the non pharmacological side effect profile of bicalutamide is not dissimilar to that of placebo Table m 3 Lunglmayr G August 1995 Efficacy and tolerability of Casodex in patients with advanced prostate cancer International Casodex Study Group Anti Cancer Drugs 6 4 508 13 doi 10 1097 00001813 199508000 00003 PMID 7579554 McLeod DG 1997 Tolerability of Nonsteroidal Antiandrogens in the Treatment of Advanced Prostate Cancer Oncologist 2 1 18 27 doi 10 1634 theoncologist 2 1 18 PMID 10388026 DeAngelis LM Posner JB 12 September 2008 Neurologic Complications of Cancer Oxford University Press USA pp 479 ISBN 978 0 19 971055 3 Archived from the original on 7 May 2016 Jamnicky L Nam R 5 November 2012 Canadian Guide to Prostate Cancer John Wiley amp Sons pp 177 ISBN 978 1 118 51565 5 Tyrrell CJ Denis L Newling D Soloway M Channer K Cockshott ID 1998 Casodex 10 200 mg daily used as monotherapy for the treatment of patients with advanced prostate cancer An overview of the efficacy tolerability and pharmacokinetics from three phase II dose ranging studies Casodex Study Group Eur Urol 33 1 39 53 doi 10 1159 000019526 PMID 9471040 S2CID 71758492 Tyrrell CJ Iversen P Tammela T Anderson J Bjork T Kaisary AV Morris T September 2006 Tolerability efficacy and pharmacokinetics of bicalutamide 300 mg 450 mg or 600 mg as monotherapy for patients with locally advanced or metastatic prostate cancer compared with castration BJU International 98 3 563 72 doi 10 1111 j 1464 410X 2006 06275 x PMID 16771791 S2CID 41672303 a b See WA Wirth MP McLeod DG Iversen P Klimberg I Gleason D et al August 2002 Bicalutamide as immediate therapy either alone or as adjuvant to standard care of patients with localized or locally advanced prostate cancer first analysis of the early prostate cancer program The Journal of Urology 168 2 429 35 doi 10 1016 S0022 5347 05 64652 6 PMID 12131282 Schellhammer P Sharifi R Block N Soloway M Venner P 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00003495 200666060 00007 PMID 16706554 S2CID 46966712 Iversen P Johansson JE Lodding P Kylmala T Lundmo P Klarskov P Tammela TL Tasdemir I Morris T Armstrong J 2006 Bicalutamide 150 mg in addition to standard care for patients with early non metastatic prostate cancer updated results from the Scandinavian Prostate Cancer Period Group 6 Study after a median follow up period of 7 1 years Scandinavian Journal of Urology and Nephrology 40 6 441 52 doi 10 1080 00365590601017329 PMID 17130095 S2CID 25862814 a b Trueb RM Luu NC Uribe NC Regnier A December 2022 Comment on Bicalutamide and the new perspectives for female pattern hair loss treatment What dermatologists should know J Cosmet Dermatol 21 12 7200 7201 doi 10 1111 jocd 14936 PMID 35332669 S2CID 247677549 Indeed due to the minimal biological importance of androgens in women the adverse effects of bicalutamide are few And yet bicalutamide has been associated with elevated liver enzymes and as of 2021 there have been 10 case reports of liver toxicity associated with bicalutamide with fatality occurring in 2 cases 2 a b Gretarsdottir HM Bjornsdottir E Bjornsson ES 2018 Bicalutamide Associated Acute Liver Injury and Migratory Arthralgia A Rare but Clinically Important Adverse Effect Case Reports in Gastroenterology 12 2 266 70 doi 10 1159 000485175 ISSN 1662 0631 a b c Hussain S Haidar A Bloom RE Zayouna N Piper MH Jafri SM 2014 Bicalutamide induced hepatotoxicity A rare adverse effect Am J Case Rep 15 266 70 doi 10 12659 AJCR 890679 PMC 4068966 PMID 24967002 a b Yun GY Kim SH Kim SW Joo JS Kim JS Lee ES Lee BS Kang SH Moon HS Sung JK Lee HY Kim KH April 2016 Atypical onset of bicalutamide induced liver injury World J Gastroenterol 22 15 4062 5 doi 10 3748 wjg v22 i15 4062 PMC 4823258 PMID 27099451 a b O Bryant CL Flaig TW Utz KJ 2008 Bicalutamide associated fulminant hepatotoxicity Pharmacotherapy 28 8 1071 5 doi 10 1592 phco 28 8 1071 PMID 18657023 S2CID 20315801 Castro Beza I Sanchez Ruiz J Peracaula Espino FJ 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insulin resistance in non obese women with polycystic ovarian syndrome and effect of bicalutamide on hirsutism CRP levels and insulin resistance Hormone Research 62 6 283 7 doi 10 1159 000081973 PMID 15542929 S2CID 46261843 a b Nurse Practitioner s Drug Handbook Springhouse Corp 2000 ISBN 9780874349979 a b c Tyrrell CJ Iversen P Tammela T Anderson J Bjork T Kaisary AV Morris T September 2006 Tolerability efficacy and pharmacokinetics of bicalutamide 300 mg 450 mg or 600 mg as monotherapy for patients with locally advanced or metastatic prostate cancer compared with castration BJU International 98 3 563 72 doi 10 1111 j 1464 410X 2006 06275 x PMID 16771791 S2CID 41672303 Griffith HW 2008 Complete Guide to Prescription amp Nonprescription Drugs 2009 HP Books pp 62 ISBN 978 0 399 53463 8 Overdose unlikely to threaten life with NSAAs Genrx 1999 1999 Mosby s GenRx Mosby ISBN 978 0 323 00625 5 A 79 year old man attempted suicide by ingesting 13g of nilutamide i e 43 times the maximum recommended dose Despite immediate gastric lavage and oral administration of activated charcoal plasma nilutamide levels peaked at 6 times the normal range 2 hours after ingestion There were no clinical signs or symptoms or changes in parameters such as transaminases or chest x ray Maintenance treatment 150 mg day was resumed 30 days later a b c d e f g h i Weber GF 22 July 2015 Molecular Therapies of Cancer Springer pp 318 ISBN 978 3 319 13278 5 Compared to flutamide and nilutamide bicalutamide has a 2 fold increased affinity for the Androgen Receptor a longer half life and substantially reduced toxicities Based on a more favorable safety profile relative to flutamide bicalutamide is indicated for use in combination therapy with a Gonadotropin Releasing Hormone analog for the treatment of advanced metastatic prostate carcinoma Mosby s GenRx A Comprehensive Reference for Generic and Brand Prescription Drugs Mosby 2001 p 290 ISBN 978 0 323 00629 3 In vitro studies have shown 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in patients with benign prostatic hyperplasia British Journal of Urology 75 3 335 40 doi 10 1111 j 1464 410X 1995 tb07345 x PMID 7537602 Wein AJ Kavoussi LR Novick AC Partin AW Peters CA 25 August 2011 Campbell Walsh Urology Expert Consult Premium Edition Enhanced Online Features and Print 4 Volume Set Elsevier Health Sciences pp 2938 2939 2946 ISBN 978 1 4160 6911 9 Archived from the original on 5 May 2016 a b Diamanti Kandarakis E Nestler JE Pandas D Pasquale R 21 December 2009 Insulin Resistance and Polycystic Ovarian Syndrome Pathogenesis Evaluation and Treatment Springer Science amp Business Media pp 75 ISBN 978 1 59745 310 3 Archived from the original on 19 May 2016 li, wikipedia, wiki, book, books, library,

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