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Bicalutamide

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| _countSecondIDs={{#invoke:ParameterCount |main |CAS_number2 |ATC_prefix2 |PubChem2 |PubChemStructure2 |IUPHAR_ligand2 |DrugBank2 |ChemSpiderID2 |UNII2 |KEGG2 |ChEBI2 |ChEMBL2 |PDB_ligand2 |NIAID_ChemDB2 |SMILES2 |smiles2 |StdInChI2 |StdInChIKey2 |DTXCID2}} | _countIndexlabels={{#invoke:ParameterCount |main |index_label |index2_label}} | _trackListSortletter= |QID = |QID2 = |Verifiedfields=verified |Watchedfields=verified |verifiedrevid=459978482}} Bicalutamide, sold under the brand name Casodex among others, is an antiandrogen medication that is primarily used to treat prostate cancer.<ref name=AHFS2016>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is typically used together with a gonadotropin-releasing hormone (GnRH) analogue or surgical removal of the testicles to treat metastatic prostate cancer (mPC).<ref name=WassStewart2011>Template:Cite book</ref><ref name=AHFS2016/><ref name="ShergillArya2010">Template:Cite book</ref> To a lesser extent, it is used at high doses for locally advanced prostate cancer (LAPC) as a monotherapy without castration.<ref name="LemkeWilliams2008" /><ref name="Cockshott2004" /><ref name="Wellington2006" /> Bicalutamide was also previously used as monotherapy to treat localized prostate cancer (LPC), but authorization for this use was withdrawn following unfavorable trial findings.<ref name="Wellington2006" /><ref name="pmid18093474" /><ref name="BowsherCarter2008" /><ref name="NargundRaghavan2015" /> Besides prostate cancer, bicalutamide is limitedly used in the treatment of excessive hair growth and scalp hair loss in women,<ref name=WilliamsBigby2009>Template:Cite book</ref><ref name="pmid35032336">Template:Cite journal</ref> as a puberty blocker and component of feminizing hormone therapy for transgender girls and women,<ref name="pmid30256230">Template:Cite journal</ref> to treat gonadotropin-independent early puberty in boys,<ref name=JamesonGroot2015>Template:Cite book</ref> and to prevent overly long-lasting erections in men.<ref name=YuanDeSouza2008>Template:Cite journal</ref> It is taken by mouth.<ref name=AHFS2016 />

Common side effects of bicalutamide in men include breast growth, breast tenderness, and hot flashes.<ref name=AHFS2016 /> Other side effects in men include feminization and sexual dysfunction.<ref name="pmid20626600">Template:Cite journal</ref><ref name="HammererManka2019">Template:Cite book</ref> Some side effects like breast changes and feminization are minimal when combined with castration.<ref name="DrozAudisio2012">Template:Cite book</ref> 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.<ref name="Shapiro2012">Template:Cite book</ref><ref name=AHFS2016/> Use during pregnancy may harm the baby.<ref name=AHFS2016 /> In men with early prostate cancer, bicalutamide monotherapy has been found to increase the likelihood of death from causes other than prostate cancer.<ref name="pmid35569476" /><ref name="Wellington2006" /> Bicalutamide produces abnormal liver changes necessitating discontinuation in around 1% of people.<ref name="FDALabel">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=Wellington2006>Template:Cite journal</ref> Rarely, it has been associated with cases of serious liver damage,<ref name=AHFS2016 /> serious lung toxicity,<ref name=Dart2004 /> and sensitivity to light.<ref name="LeeOda2016">Template:Cite journal</ref><ref name="ReactionsWeekly2016">Template:Cite journal</ref> Although the risk of adverse liver changes is small, monitoring of liver function is recommended during treatment.<ref name=AHFS2016 />

Bicalutamide is a member of the nonsteroidal antiandrogen (NSAA) group of medications.<ref name=Dart2004>Template:Cite book</ref> It works by selectively blocking the androgen receptor (AR), the biological target of the androgen sex hormones testosterone and dihydrotestosterone (DHT).<ref name=SinghGauthier2000>Template:Cite journal</ref> It does not lower androgen levels.<ref name=Dart2004 /> The medication can have some estrogen-like effects in men when used as a monotherapy due to increased estradiol levels.<ref name="IIIBarbieri2013a">Template:Cite book</ref><ref name="MarcusFeldman2007" /><ref name="MahlerVerhelst1998" /> Bicalutamide is well-absorbed, and its absorption is not affected by food.<ref name=Cockshott2004 /> The elimination half-life of the medication is around one week.<ref name="Cockshott2004" /><ref name=AHFS2016 /> It shows peripheral selectivity in animals, but crosses the blood–brain barrier and affects both the body and brain in humans.<ref name=Cockshott2004 /><ref name="FurrTucker1996"/>

Bicalutamide was patented in 1982 and approved for medical use in 1995.<ref name=FischerGanellin2006>Template:Cite book</ref> It is on the World Health Organization's List of Essential Medicines.<ref name="WHO21st">Template:Cite book</ref> Bicalutamide is available as a generic medication.<ref name=Ric2015>Template:Cite book</ref> The drug is sold in more than 80 countries, including most developed countries.<ref name="Drugs.com-2">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=Ak1999>Template:Cite journal</ref><ref name="AstraZeneca1999">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="HammererManka2019" /><ref name=MukherjiPezaro2012>Template:Cite journal</ref><ref name=PchejetskiAlshaker2014>Template:Cite journal</ref><ref name="Campbell2014">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=HHS2010>Template:Citation</ref> Although bicalutamide is also used for other indications besides prostate cancer, the vast majority of prescriptions appear to be for treatment of prostate cancer.<ref name="HHS2010" />

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Medical usesEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

Bicalutamide is approved for and mainly used in the following indications:<ref name="BagatellBremner2003" />

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.<ref name="SuzukiKamiya2008" /><ref name="pmid17199134" />

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 formsEdit

Bicalutamide is available for the treatment of prostate cancer in most developed countries,<ref name="IndexNominum2000">Template:Cite book</ref><ref name="Drugs.com-2"/><ref name="Martindale2011">Template:Cite book</ref> including over 80 countries worldwide.<ref name=Ak1999/><ref name="AstraZeneca1999"/> It is available in 50 mg, 80 mg (in Japan),<ref name="SuzukiKamiya2008">Template:Cite journal</ref> and 150 mg tablets for oral administration.<ref name="WhiteBradnam2015">Template:Cite book</ref><ref name="MortonHall2001">Template:Cite book</ref> The drug is registered for use as a 150 mg/day monotherapy for the treatment of Template:Abbr in at least 55 countries,<ref name="Cockshott2004" /> with the Template:Abbr being a notable exception where it is registered only for use at a dosage of 50 mg/day in combination with castration.<ref name="ChabnerLongo2010">Template:Cite book</ref> No other formulations or routes of administration are available or used.<ref name="WhiteBradnam2015" /> All formulations of bicalutamide are specifically indicated for the treatment of prostate cancer alone or in combination with surgical or medication castration.<ref name="LemkeWilliams2008" /> 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.<ref name="pmid12496872">Template:Cite journal</ref><ref name="Cockshott2004" />

A combined formulation of bicalutamide and the [[GnRH agonist|Template:Abbr 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).<ref name="Martindale2011" /><ref name="Drugs.com-3">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="ZolacosCPLabelAu">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name="ZolacosCPLabelNZ">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

ContraindicationsEdit

Bicalutamide is pregnancy category X, or "contraindicated in pregnancy", in the Template:Abbr,<ref name="FDALabel" /> and pregnancy category D, the second most restricted rating, in Australia.<ref name="TGALabel" /> 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.<ref name="IswaranImai1997" /><ref name="Smith2013" /> 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.<ref name="Dart2004" /><ref name="FDALabel" />

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.<ref name="Cockshott2004" /><ref name="SkeelKhleif2011">Template:Cite book</ref> 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).<ref name="Wellington2006" /><ref>Template:Cite book</ref><ref name="PDR2004">Template:Cite book</ref> The elimination half-life of bicalutamide is unchanged in renal impairment.<ref name="ChabnerLongo2010" />

Side effectsEdit

{{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}} Template:Major side effects of bicalutamide alone

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.<ref name="Lehne2013">Template:Cite book</ref><ref name="WirthHakenberg2007">Template:Cite journal</ref> 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.<ref name="WirthHakenberg2007" /><ref name="WellingtonKeam2006">Template:Cite journal</ref> 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.<ref name="Lehne2013" /><ref name="Higano2003">Template:Cite journal</ref><ref name="pmid20626600" /><ref name="pmid23008326">Template:Cite journal</ref> 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.<ref name="Lehne2013" /><ref name="Kolvenbag1996">Template:Cite journal</ref><ref name="ResnickThompson2000">Template:Cite book</ref> However, most men have preserved sexual function with bicalutamide monotherapy.<ref name="IversenMelezinek2001" /><ref name="pmid12603397a" /> In females, due to the minimal biological importance of androgens in this sex,<ref name="pmid28343552">Template:Cite journal</ref><ref name="pmid26358173">Template:Cite journal</ref> the side effects of pure antiandrogens or Template:Abbr are few, and bicalutamide has been found to be very well tolerated.<ref name="Shapiro2012" /> However, bicalutamide has been found to increase levels of total and LDL cholesterol in women.<ref name="pmid33334002">Template:Cite journal</ref><ref name="pmid33070640">Template:Cite journal</ref><ref name="pmid29211888" /> 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.<ref name="FourcadeMcLeod2004">Template:Cite journal</ref> 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.<ref name="Kolvenbag1996" /><ref name="Dart2004" /><ref name="pmid7579554">Template:Cite journal</ref><ref name="pmid10388026">Template:Cite journal</ref><ref name="MDMD2008">Template:Cite book</ref><ref name="JamnickyNam2012">Template:Cite book</ref> The drug is well-tolerated at higher dosages than 50 mg/day, up to 600Template:Nbspmg/day, with rare additional side effects.<ref name="ChabnerLongo2010" /><ref name="pmid9471040">Template:Cite journal</ref><ref name="TyrrellIversen2006">Template:Cite journal</ref>

Bicalutamide has been associated with abnormal liver function tests such as elevated liver enzymes.<ref name="Kolvenbag1996" /><ref name="Wellington2006" /> In the Early Prostate Cancer (EPC) clinical programme of bicalutamide for Template:Abbr and Template:Abbr, the rate of abnormal liver function tests with bicalutamide monotherapy was 3.4% relative to 1.9% for placebo.<ref name="Wellington2006" /><ref name="SeeWirth2002">Template:Cite journal</ref> However, higher rates, up to 11%, have been seen in other studies.<ref name="pmid35032336" /><ref name="FDALabel" /> 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.<ref name="FDALabel" /><ref name="Wellington2006" /><ref name="MahlerVerhelst1998" /><ref name="SeeWirth2002" /><ref name="pmid8560679">Template:Cite journal</ref> Elevated liver enzymes with bicalutamide usually occur within the first 3 to 6 months of treatment.<ref name="Kolvenbag1996" /><ref name="FDALabel" /> Monitoring of liver function during treatment is recommended, particularly in the first few months.<ref name="Wellington2006" /><ref name="Lehne2013" /> In men with early prostate cancer, bicalutamide monotherapy has been found to increase non-prostate cancer mortality.<ref name="pmid35569476">Template:Cite journal</ref><ref name="IversenJohansson2004">Template:Cite journal</ref><ref name="Wellington2006" /> 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.<ref name="pmid16706554">Template:Cite journal</ref><ref name="pmid17130095">Template:Cite journal</ref>

There are 10 published case reports of liver toxicity associated with bicalutamide as of 2022.<ref name="pmid35332669">Template:Cite journal</ref><ref name="GretarsdottirBjornsdottir2018">Template:Cite journal</ref><ref name="pmid24967002">Template:Cite journal</ref><ref name="pmid27099451">Template:Cite journal</ref> Death occurred in 2 of these cases.<ref name="pmid35332669" /><ref name="pmid18657023">Template:Cite journal</ref><ref name="pmid18796378">Template:Cite journal</ref> Hundreds of additional cases of liver complications in people taking bicalutamide exist in the FDA Adverse Event Reporting System (FAERS) database.<ref name="FAERS">Template:Cite journal</ref> In all of the published case reports of liver toxicity with bicalutamide, the onset of symptoms was within the first 6 months of treatment.<ref name="GretarsdottirBjornsdottir2018" /><ref name="pmid24967002" /><ref name="pmid27099451" /> Symptoms that may indicate liver dysfunction include nausea, vomiting, abdominal pain, fatigue, anorexia, "flu-like" symptoms, dark urine, and jaundice.<ref name="FDALabel" /> There are also published case reports of interstitial pneumonitis and eosinophilic lung disease associated with bicalutamide.<ref name="Dart2004b">Template:Cite book</ref><ref name="MasagoWatanabe2011">Template:Cite journal</ref><ref name="Aronson2014">Template:Cite book</ref> along with hundreds of additional instances in the FAERS database as well.<ref name="FAERS" /> 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).<ref name="pmid15195196">Template:Cite journal</ref> The exact incidence of liver toxicity and interstitial pneumonitis with bicalutamide are unknown, but both are said to be very rare events.<ref name="pmid24967002" /><ref name="TholeManso2004">Template:Cite journal</ref><ref name="RicciBuzzatti2014">Template:Cite journal</ref> A few cases of photosensitivity have been reported with bicalutamide.<ref name="LeeOda2016" /> Hypersensitivity reactions (drug allergy) like angioedema and hives have also uncommonly been reported in association with bicalutamide.<ref name="FDALabel" />

Because it is an antiandrogen, bicalutamide has a theoretical risk of birth defects like ambiguous genitalia in male fetuses.<ref name="IswaranImai1997">Template:Cite journal</ref><ref name="Smith2013">Template:Cite book</ref><ref>Template:Cite book</ref><ref name="Paoletti2012">Template:Cite book</ref> Due to its teratogenic capacity, contraception should be used in women taking bicalutamide who are fertile and sexually active.<ref name="PapadimitriouAnagnostisGoulis2022">Template:Cite book</ref>

ComparisonEdit

Template:See also

The side effect profile of bicalutamide in men and women differs from that of other antiandrogens and is considered favorable in comparison.<ref name="RamonDenis2007">Template:Cite book</ref><ref name="pmid12603397a">Template:Cite journal</ref><ref name="Moser2008">Template:Cite book</ref><ref name="Demos2011">Template:Cite book</ref> Relative to Template:Abbr analogues and the steroidal antiandrogen (SAA) cyproterone acetate (CPA), bicalutamide monotherapy has a much lower incidence and severity of hot flashes and sexual dysfunction.<ref name="IversenMelezinek2001" /><ref name="pmid12603397a" /><ref name="WellingtonKeam2006" /><ref name="Aronson2009">Template:Cite book</ref> In addition, unlike Template:Abbr analogues and Template:Abbr, bicalutamide monotherapy is not associated with decreased bone mineral density or osteoporosis.<ref name="WellingtonKeam2006" /><ref name="pmid12603397a" /> Conversely, bicalutamide monotherapy is associated with much higher rates of breast tenderness, gynecomastia, and feminization in men than Template:Abbr analogues and Template:Abbr.<ref name="WellingtonKeam2006" /> However, gynecomastia with bicalutamide is rarely severe and discontinuation rates due to this side effect are fairly low.<ref name="WellingtonKeam2006" /><ref name="pmid12603397a" /> These differences in side effects between bicalutamide monotherapy, Template:Abbr analogues, and Template:Abbr are attributed to the fact that whereas Template:Abbr analogues and Template:Abbr suppress estrogen production, bicalutamide monotherapy does not lower estrogen levels and in fact actually increases them.<ref name="WellingtonKeam2006" />

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 Template:Abbr has been associated with.<ref name="Aronson2009" /><ref name="Barrett2007">Template:Cite book</ref><ref name="pmid12190640">Template:Cite journal</ref><ref name="pmid10936469">Template:Cite journal</ref> It has a much lower risk of hepatotoxicity than flutamide and Template:Abbr and of interstitial pneumonitis than nilutamide.<ref name="pmid15604569">Template:Cite journal</ref><ref name="pmid12603397a" /><ref name="pmid18657023" /><ref name="CRAIGFurr2010">Template:Cite book</ref><ref name="Bennett_2002">Template:Cite journal</ref><ref name="pmid25270521">Template:Cite journal</ref> The drug also does not share the unique risks of diarrhea with flutamide and nausea, vomiting, visual disturbances, and alcohol intolerance with nilutamide.<ref name="pmid12603397a" /><ref name="Aronson2009" /><ref name="CRAIGFurr2010" /> Unlike enzalutamide, bicalutamide is not associated with seizures or related central side effects like anxiety and insomnia.<ref name="pmid20878947">Template:Cite journal</ref><ref name="pmid24881730">Template:Cite journal</ref> 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.<ref name="pmid25711765">Template:Cite journal</ref><ref name="pmid25354111">Template:Cite journal</ref> In contrast to the Template:Abbr spironolactone, bicalutamide does not have antimineralocorticoid effects,<ref name="pmid8560673">Template:Cite journal</ref> and hence is not associated with hyperkalemia, urinary frequency, dehydration, hypotension, or other related side effects.<ref name="LenzShulman2010">Template:Cite journal</ref><ref name="Greenblatt1973">Template:Cite journal</ref><ref name="MunozCruz2014">Template:Cite book</ref><ref name="Aronson2009" /> In women, unlike Template:Abbr and spironolactone, bicalutamide does not produce menstrual irregularity or amenorrhea and does not interfere with ovulation or fertility.<ref name="pmid24455796"/><ref name="BahceciTuzcu2004">Template:Cite journal</ref>

OverdoseEdit

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.<ref name="FDALabel" /><ref name="Springhouse2000">Template:Cite book</ref> Dosages of up to 600 mg/day have been well tolerated in clinical trials,<ref name="TYRRElLIversen2006" /> 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.<ref name="Cockshott2004" /><ref name="TYRRElLIversen2006" /> Overdose is considered unlikely to be life-threatening with bicalutamide or other first-generation Template:Abbr (i.e., flutamide and nilutamide).<ref name="Griffith2008">Template:Cite book</ref> 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.<ref name="Genrx1999">Template:Cite book</ref> There is no specific antidote for bicalutamide or Template:Abbr overdose, and treatment should be based on symptoms, if any are present.<ref name="FDALabel" /><ref name="Springhouse2000" />

InteractionsEdit

Bicalutamide is almost exclusively metabolized by CYP3A4.<ref name="LemkeWilliams2008" /> As such, its levels in the body may be altered by inhibitors and inducers of CYP3A4.<ref name="Skidmore-Roth2013">Template:Cite book</ref> (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.<ref name="Wellington2006" />

In-vitro studies suggest that bicalutamide may be able to inhibit CYP3A4 and, to a lesser extent, CYP2C9, CYP2C19, and CYP2D6.<ref name="Cockshott2004" /> Conversely, animal studies suggest that bicalutamide may induce cytochrome P450 enzymes.<ref name="Cockshott2004" /> 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.<ref name="Cockshott2004" /> 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.<ref name="Cockshott2004" /> There is no indication of clinically significant enzyme inhibition or induction with bicalutamide at doses of 150Template:Nbspmg/day or below.<ref name="Cockshott2004" />

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.<ref name="WirthHakenberg2007" /><ref name="Kolvenbag1996" /> This could, in turn, result in increased free concentrations of such drugs and increased effects and/or side effects, potentially necessitating dosage adjustments.<ref name="WirthHakenberg2007" /> 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. This is supported by reports of prolonged prothrombin time and internal bleeding after the introduction of bicalutamide in patients previously stable on coumarin anticoagulants.<ref name="FDALabel" /> Close monitoring of prothrombin time and dosage adjustment as necessary is recommended when bicalutamide is used in combination with these drugs.<ref name="Weber2015">Template:Cite book</ref><ref name="Mosby2001">Template:Cite book</ref><ref name="SprattoWoods2008">Template:Cite book</ref> 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.<ref name="Kolvenbag1996" />

PharmacologyEdit

PharmacodynamicsEdit

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Antiandrogenic activityEdit

Bicalutamide acts as a highly selective competitive silent antagonist of the Template:Abbr (Template:Abbrlink = 159–243 nM), the major biological target of the androgen sex hormones testosterone and Template:Abbrlink, and hence is an antiandrogen.<ref name="SinghGauthier2000" /><ref name="Balaji2016">Template:Cite book</ref><ref name="MasielloCheng2002">Template:Cite journal</ref><ref name="Denis2012">Template:Cite book</ref> The activity of bicalutamide lies in the (R)-isomer.<ref name="SchellensMcLeod2005" /> Due to its selectivity for the Template:Abbr, 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).<ref name="Becker2001">Template:Cite book</ref><ref name="FurrTucker1996">Template:Cite journal</ref><ref name="SchellensMcLeod2005">Template:Cite book</ref><ref name="BagatellBremner2003">Template:Cite book</ref> 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.<ref name="pmid29497605">Template:Cite journal</ref> Bicalutamide does not inhibit 5α-reductase nor is known to inhibit other enzymes involved in androgen steroidogenesis (e.g., CYP17A1).<ref name="Furr1995" /> Although it does not bind to the estrogen receptors (ERs), bicalutamide can increase estrogen levels secondarily to Template:Abbr blockade when used as a monotherapy in males, and hence can have some indirect estrogenic effects in males.<ref name="pmid18231613">Template:Cite journal</ref> 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 Template:Abbr.<ref name="Dart2004" /><ref name="Becker2001" /><ref name="SchellensMcLeod2005" /> In addition to the classical nuclear Template:Abbr, bicalutamide has been assessed at the membrane androgen receptors (mARs) and found to act as a potent antagonist of ZIP9 (Template:Abbr = 66.3 nM), whereas it does not appear to interact with GPRC6A.<ref name="pmid28943399">Template:Cite journal</ref><ref name="pmid20947496">Template:Cite journal</ref>

The affinity of bicalutamide for the Template:Abbr is relatively low as it is approximately 30 to 100 times lower than that of Template:Abbr, which is 2.5- to 10-fold as potent as an Template:Abbr agonist as testosterone in bioassays and is the main endogenous ligand of the receptor in the prostate gland.<ref name="Furr2009">Template:Cite journal</ref><ref name="Denis2012" /><ref name="Cockshott2004" /><ref name="pmid19359544">Template:Cite journal</ref> However, typical clinical dosages of bicalutamide result in circulating levels of the drug that are thousands of times higher than those of testosterone and Template:Abbr, allowing it to powerfully prevent them from binding to and activating the receptor.<ref name="Furr1997">Template:Cite journal</ref><ref name="FiggChau2010">Template:Cite book</ref><ref name="FurrTucker1996" /><ref name="pmid8717469">Template:Cite journal</ref><ref name="FDALabel" /><ref name="TGALabel" /><ref name="DenisMahler1996" /><ref name="Wellington2006" /><ref name="pmid15838655">Template:Cite journal</ref> This is especially true in the case of surgical or medical castration, in which testosterone levels in the circulation are approximately 95% reduced and Template:Abbr levels in the prostate gland are about 50 to 60% reduced.<ref name="Denis2012" /><ref name="LuoMartel1997">Template:Cite journal</ref> In women, levels of testosterone are substantially lower (20- to 40-fold) than in men,<ref name="MelmedPolonsky2015">Template:Cite book</ref> so much smaller doses of bicalutamide (e.g., 25 mg/day in the hirsutism studies) are necessary.<ref name="WilliamsBigby2009" /><ref name="pmid24455796" /><ref name="MorettiGuccione2016">Template:Cite conference</ref><ref name="MahlerVerhelst1998" />

Blockade of the Template:Abbr 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.<ref name="IversenMelezinek2001">Template:Cite journal</ref> This, in turn, results in an increase in circulating Template:Abbr levels and activation of the gonadal production of testosterone and by extension production of estradiol.<ref name="pmid7537602">Template:Cite journal</ref> 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.<ref name="IIIBarbieri2013a" /><ref name="MarcusFeldman2007">Template:Cite book</ref><ref name="MahlerVerhelst1998">Template:Cite journal</ref> In addition to testosterone and estradiol, there are smaller increases in concentrations of Template:Abbr, sex hormone-binding globulin, and prolactin.<ref name="MahlerVerhelst1998" /> 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.<ref name="MarcusFeldman2007" /><ref name="WeinKavoussi2011">Template:Cite book</ref><ref name="Becker2001" /> Testosterone concentrations do not typically exceed the normal male range due to negative feedback on the Template:Abbr axis by the increased concentrations of estradiol.<ref name="IversenMelezinek2001" /> Bicalutamide influences the Template:Abbr axis and increases hormone levels only in men and not also in women.<ref name="Diamanti-KandarakisNestler2009">Template:Cite book</ref><ref name="CarrellPeterson2010">Template:Cite book</ref><ref name="BouchardCaraty1993">Template:Cite book</ref> This is due to the much lower levels of androgens in women and their lack of basal suppression of the Template:Abbr axis in this sex.<ref name="Diamanti-KandarakisNestler2009" /><ref name="CarrellPeterson2010" /><ref name="BouchardCaraty1993" /> 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.<ref name="ChabnerLongo2010" /> However, the elevated levels of estradiol remain unopposed by bicalutamide and are responsible for the gynecomastia and feminizing side effects it causes in men.<ref name="pmid18062751">Template:Cite journal</ref> 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 Template:Abbr analogue, estrogen, or progestogen, as these medications maintain negative feedback on the HPG axis.<ref name="Melmed2016">Template:Cite book</ref><ref name="AsschemanGooren1989">Template:Cite journal</ref><ref name="Raode Voogt1988">Template:Cite journal</ref>

Template:Abbr 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 Template:Abbr analogues than with Template:Abbr monotherapy. It is thought that this is because Template:Abbr analogues suppress estrogen production in addition to androgen production, resulting in estrogen deficiency.<ref name="WibowoSchellhammer2011">Template:Cite journal</ref><ref name="MotofeiRowland2011">Template:Cite journal</ref><ref name="pmid23484454">Template:Cite journal</ref> In contrast, Template:Abbr 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.<ref name="WibowoSchellhammer2011" /><ref name="MotofeiRowland2011" /><ref name="pmid23484454" /> Neurosteroids that are produced from testosterone like 3α-androstanediol and 3β-androstanediol, which are Template:Abbrlink agonists and the former a potent GABAA receptor positive allosteric modulator, may also be involved.<ref name="King2008">Template:Cite journal</ref><ref name="pmid7803627">Template:Cite journal</ref><ref name="pmid20646182">Template:Cite journal</ref><ref name="Chedrese2009">Template:Cite book</ref><ref name="pmid20552051">Template:Cite journal</ref><ref name="HuangZhu2008">Template:Cite journal</ref><ref name="FryeKoonce2008">Template:Cite journal</ref> In the specific case of sexual dysfunction, an additional possibility for the difference is that without concomitant suppression of androgen production, blockade of the Template:Abbr by the bicalutamide in the brain is incomplete and insufficient to markedly influence sexual function.<ref name="pmid9592622">Template:Cite journal</ref>

Under normal circumstances, bicalutamide has no capacity to activate the Template:Abbr.<ref name="pmid25797385">Template:Cite journal</ref><ref name="BamburyRathkopf2015">Template:Cite journal</ref> However, in prostate cancer, mutations and overexpression of the Template:Abbr can accumulate in prostate gland cells which can convert bicalutamide from an antagonist of the Template:Abbr into an agonist.<ref name="pmid25797385" /><ref name="pmid24100689">Template:Cite journal</ref> 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.<ref name="pmid25797385" /><ref name="pmid24100689" />

In transgender women, breast development is a desired effect of antiandrogen or estrogen treatment.<ref name="WierckxGooren2014" /><ref name="OrentreichDurr1974">Template:Cite journal</ref> Breast development and gynecomastia induced by bicalutamide is thought to be mediated by increased activation of the Template:Abbr secondary to blockade of the Template:Abbr (resulting in disinhibition of the Template:Abbr in breast tissue) and increased levels of estradiol.<ref name="JamesonGroot2015" /><ref name="IIIBarbieri2013b">Template:Cite book</ref><ref name="WilsonNizet2015">Template:Cite book</ref> In addition to fat deposition, connective tissue growth, and ductal development, bicalutamide has been found to produce moderate lobuloalveolar development of the breasts.<ref name="KanhaiHage2000">Template:Cite journal</ref><ref name="Lawrence2007">Template:Cite book</ref><ref name="Rosen2009">Template:Cite book</ref> However, full lobuloalveolar maturation necessary for lactation and breastfeeding will not occur without progestogen treatment.<ref name="KanhaiHage2000" /><ref name="Lawrence2007" /><ref name="Rosen2009" />

Bicalutamide monotherapy seems to have minimal effect on testicular spermatogenesis, testicular ultrastructure, and certain aspects of male fertility.<ref name="Mulhall2013">Template:Cite book</ref><ref name="IswaranImai1997" /><ref name="MorganteGradini2001">Template:Cite journal</ref> 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.<ref name="SchillComhaire2006">Template:Cite book</ref><ref name="NieschlagBehre2012">Template:Cite book</ref><ref name="Cheng2009">Template:Cite book</ref> 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.<ref name="SchillComhaire2006" /><ref name="NieschlagBehre2012" /><ref name="Cheng2009" /> However, while bicalutamide does not seem to be able to adversely influence testicular spermatogenesis, it may interfere with Template:Abbr-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.<ref name="NeumannSchenck1980">Template:Cite book</ref> In addition, the combination of bicalutamide with other medications, such as estrogens, progestogens, and Template:Abbr analogues, can compromise spermatogenesis due to their own adverse effects on male fertility.<ref name="Johnson2003">Template:Cite book</ref><ref name="JonesReiter2016">Template:Cite journal</ref><ref name="PayneHardy2007">Template:Cite book</ref><ref name="WakelinMaibach2002">Template:Cite book</ref><ref name="pmid8005205">Template:Cite journal</ref><ref name="Salam2003">Template:Cite book</ref> 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.<ref name="Johnson2003" /><ref name="JonesReiter2016" /><ref name="PayneHardy2007" /><ref name="WakelinMaibach2002" /><ref name="pmid8005205" /><ref name="Salam2003" />

Other activitiesEdit

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.<ref name="Cockshott2004" /> 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.<ref name="pmid26082378">Template:Cite journal</ref><ref name="MastZheng2013">Template:Cite journal</ref> Bicalutamide has been found to be a P-glycoprotein (ABCB1) inhibitor.<ref name="ZhuLiu2015">Template:Cite journal</ref><ref name="Fenner2015">Template:Cite journal</ref><ref name="pmid26309896">Template:Cite journal</ref> Like other first-generation Template:Abbr and enzalutamide, it has been found to act as a weak non-competitive inhibitor of GABAA receptor-mediated currents in vitro (Template:Abbr = 5.2 μM).<ref name="FosterCar2011">Template:Cite journal</ref><ref name="BarrishCarter2010">Template:Cite book</ref> 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.<ref name="FosterCar2011" /><ref name="BarrishCarter2010" />

PharmacokineticsEdit

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Though its absolute bioavailability in humans is unknown, bicalutamide is known to be extensively and well-absorbed.<ref name="Cockshott2004" /><ref name="Dart2004" /> Its absorption is not affected by food.<ref name="Dart2004" /><ref name="Weber2015" /> 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.<ref name="Cockshott2004" /><ref name="Wellington2006" /><ref name="KolvenbagBlackledge1998">Template:Cite journal</ref><ref name="TYRRElLIversen2006">Template:Cite journal</ref> 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.<ref name="Wellington2006" /><ref name="FDALabel" /><ref name="Cockshott2004" /> 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.<ref name="Wellington2006" /><ref name="pmid8717470">Template:Cite journal</ref><ref name="Jr.Lawrence2015">Template:Cite book</ref><ref name="DenisMahler1996">Template:Cite journal</ref> The long time to steady-state levels is the result of bicalutamide's very long elimination half-life.<ref name="DenisMahler1996" /> There is wide interindividual variability in (R)-bicalutamide levels (up to 16-fold) with bicalutamide regardless of dosage.<ref name="Cockshott2004" />

The tissue distribution of bicalutamide is not well-characterized.<ref name="ChuJr.2012">Template:Cite book</ref> 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.<ref name="TGALabel" /> 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.<ref name="HelsenVan den Broeck2014">Template:Cite journal</ref><ref name="FurrTucker1996" /><ref name="Furr1989">Template:Cite journal</ref><ref name="FurrValcaccia1987">Template:Cite journal</ref> As such, it was initially thought to be a peripherally selective antiandrogen.<ref name="HelsenVan den Broeck2014" /><ref name="FurrTucker1996" /> 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.<ref name="Cockshott2004" /><ref name="IversenMelezinek2001" /><ref name="SolowaySchellhammer1995">Template:Cite journal</ref><ref name="GaoDalton2007">Template:Cite journal</ref><ref name="pmid16896883">Template:Cite journal</ref> In any case, there is indication that bicalutamide might have at least some peripheral selectivity in humans.<ref name="pmid20682842">Template:Cite journal</ref> 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 Template:Abbr and corticosteroid-binding globulin.<ref name="LemkeWilliams2008" /><ref name="Cockshott2004" /><ref name="ChuJr.2012" /><ref name="Furr1995">Template:Cite journal</ref>

Bicalutamide is metabolized in the liver.<ref name="LemkeWilliams2008" /><ref name="Weber2015" /> (R)-Bicalutamide is metabolized slowly and almost exclusively via hydroxylation by CYP3A4 into (R)-hydroxybicalutamide.<ref name="Weber2015" /><ref name="Cockshott2004" /><ref name="LemkeWilliams2008" /><ref name="LemkeWilliams2012" /> This metabolite is then glucuronidated by UGT1A9.<ref name="Weber2015" /><ref name="Cockshott2004" /><ref name="GrosseCampeau2013">Template:Cite journal</ref><ref name="Schellhammer2005" /> In contrast to (R)-bicalutamide, (S)-bicalutamide is metabolized rapidly and mainly by glucuronidation (without hydroxylation).<ref name="Weber2015" /> None of the metabolites of bicalutamide are known to be active and levels of the metabolites are low in plasma, where unchanged biclautamide predominates.<ref name="LemkeWilliams2008" /><ref name="pmid8997470" /><ref name="Cockshott2004" /> 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.<ref name="Wellington2006" /><ref name="LemkeWilliams2012">Template:Cite book</ref><ref name="ButlerGovindan2010">Template:Cite book</ref> (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.<ref name="JordanFurr2010">Template:Cite book</ref>

Bicalutamide is eliminated in similar proportions in feces (43%) and urine (34%), while its metabolites are eliminated roughly equally in urine and bile.<ref name="LemkeWilliams2008" /><ref name="Weber2015" /><ref name="pmid14748655">Template:Cite journal</ref><ref name="pmid22495777">Template:Cite journal</ref> The drug is excreted to a substantial extent in unmetabolized form, and both bicalutamide and its metabolites are eliminated mainly as glucuronide conjugates.<ref name="SchellensMcLeod2005" /> The glucuronide conjugates of bicalutamide and its metabolites are eliminated from the circulation rapidly, unlike unconjugated bicalutamide.<ref name="Cockshott2004" /><ref name="Weber2015" /><ref name="AndersonKnoben2001">Template:Cite book</ref>

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.<ref name="Cockshott2004" /><ref name="DenisMahler1996" /> However, steady-state levels of bicalutamide are higher in Japanese individuals than in white people.<ref name="Cockshott2004" /> Template:Bicalutamide metabolism

ChemistryEdit

Bicalutamide is a racemic mixture consisting of equal proportions of enantiomers (R)-bicalutamide (dextrorotatory) and (S)-bicalutamide (levorotatory).<ref name="FDALabel" /> Its systematic name ([[IUPAC nomenclature of organic chemistry|Template:Abbr]]) is (RS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide.<ref name="Publishing2013" /><ref name="KomstaWaksmundzka-Hajnos2013">Template:Cite book</ref> 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.<ref name="FDALabel" /><ref name="TGALabel">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

The acid dissociation constant (pKa') of bicalutamide is approximately 12.<ref name="TGALabel" /> It is a highly lipophilic compound (log P = 2.92).<ref name="Cockshott2004" /><ref name="pmid21369450">Template:Cite journal</ref> 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).<ref name="FDALabel" /><ref name="TGALabel" /> In organic solvents, it is slightly soluble in chloroform and absolute ethanol, sparingly soluble in methanol, and freely soluble in acetone and tetrahydrofuran.<ref name="FDALabel" /><ref name="TGALabel" />

Bicalutamide is a synthetic and nonsteroidal compound which was derived from flutamide.<ref name="MohlerBohl2009" /> 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.<ref name="MohlerBohl2009" /><ref name="LemkeWilliams2012" /> The crystalline structure of bicalutamide is represented by a wide variety of conformation-dependent solid forms,<ref>Template:Cite journal</ref> including polymorphs,<ref>Template:Cite journal</ref> crystal solvates,<ref name=glp>Template:Cite journal</ref> co-crystals,<ref>Template:Cite journal</ref> and others. The developed structure of the aliphatic fragment promotes the formation of different conformers,<ref>Template:Cite journal</ref> thereby opening the potential for creating new solid forms with enhanced characteristics. For example, the bicalutamide solvate with DMSO demonstrated a concentration increase of up to 3.3 times compared to form I. A similar trend is observed for the metastable form II and the amorphous state, with concentrations of approximately 3.0 × 10−7 and 3.3 × 10−7 m.f., respectively, which are more than twice those of the stable form I.<ref name=glp/>

AnaloguesEdit

Template:See also

First-generation Template:Abbr including bicalutamide, flutamide, and nilutamide are all synthetic, nonsteroidal anilide derivatives and structural analogues of each other.<ref name="MohlerBohl2009">Template:Cite journal</ref> Bicalutamide is a diarylpropionamide while flutamide is a monoarylpropionamide and nilutamide is a hydantoin.<ref name="MohlerBohl2009" /> Bicalutamide and flutamide, though not nilutamide, can also be classified as toluidides.<ref name="LemkeWilliams2012" /> All three of the compounds share a common 3-trifluoromethylaniline moiety.<ref name="BéguéBonnet-Delpon2008">Template:Cite book</ref> 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.<ref name="BallKamalian2016">Template:Cite journal</ref> Topilutamide, also known as fluridil, is another Template:Abbr that is closely related structurally to the first-generation Template:Abbr, 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.<ref name="pmid16821162" /><ref name="AvramRogers2009">Template:Cite book</ref><ref name="HaberStough2006">Template:Cite book</ref>

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The second-generation Template:Abbr enzalutamide and apalutamide were derived from and are analogues of the first-generation Template:Abbr,<ref name="Weber2015" /><ref name="KawaharaMiyamoto2014">Template:Cite journal</ref> while another second-generation Template:Abbr, darolutamide, is said to be structurally distinct and chemically unrelated to the other Template:Abbr.<ref name="pmid26137992">Template:Cite journal</ref> 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.

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The first nonsteroidal androgens, the arylpropionamides, were discovered via structural modification of bicalutamide.<ref name="SegalNarayanan2006">Template:Cite journal</ref> Unlike bicalutamide (which is purely antiandrogenic), these compounds show tissue-selective androgenic effects and were classified as selective androgen receptor modulators (SARMs).<ref name="SegalNarayanan2006" /> Lead Template:Abbr of this series included acetothiolutamide, enobosarm (ostarine; S-22), and andarine (acetamidoxolutamide or androxolutamide; S-4).<ref name="MohlerBohl2009" /><ref name="SegalNarayanan2006" /><ref name="Yin2002">Template:Cite journal</ref> 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 Template:Abbr 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.<ref name="OttowWeinmann2008">Template:Cite book</ref>

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A few radiolabeled derivatives of bicalutamide have been developed for potential use as radiotracers in medical imaging.<ref name="pmid17328524">Template:Cite journal</ref><ref name="DierckxOtte2014">Template:Cite book</ref> They include [18F]bicalutamide, 4-[76Br]bromobicalutamide, and [76Br]bromo-thiobicalutamide.<ref name="pmid17328524" /><ref name="DierckxOtte2014" /> The latter two were found to have substantially increased affinity for the Template:Abbr relative to that of bicautamide.<ref name="pmid17328524" /> However, none of these agents have been evaluated in humans.<ref name="pmid17328524" /><ref name="DierckxOtte2014" />

5N-Bicalutamide, or 5-azabicalutamide, is a minor structural modification of bicalutamide which acts as a reversible covalent antagonist of the Template:Abbr and has approximately 150-fold higher affinity for the Template:Abbr and about 20-fold greater functional inhibition of the Template:Abbr relative to bicalutamide.<ref name="pmid28981251">Template:Cite journal</ref><ref name="US20170101384">Template:Cite patent</ref> It is among the most potent Template:Abbr antagonists to have been developed and is being researched for potential use in the treatment of antiandrogen-resistant prostate cancer.<ref name="pmid28981251" />

SynthesisEdit

A number of chemical syntheses of bicalutamide have been published in the literature.<ref name="Publishing2013" /><ref name="pmid3361581">Template:Cite journal</ref><ref name="JamesEkwuribe2002">Template:Cite journal</ref><ref>Template:Cite patent Template:Webarchive</ref><ref name="ChandShukla2012">Template:Cite report</ref> The procedure of the first published synthesis of bicalutamide can be seen below.<ref name="pmid3361581" /> Template:Annotated image 4

HistoryEdit

Bicalutamide as well as all of the other currently marketed Template:Abbr 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.<ref name="Diamanti-Kandarakis_1999">Template:Cite journal</ref><ref name="DenisGriffiths1999">Template:Cite book</ref><ref name="Elks2014-2">Template:Cite book</ref> 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.<ref name="pmid11844311">Template:Cite journal</ref><ref name="Furr1995" /><ref name="pmid16515480">Template:Cite journal</ref><ref name="Publishing2013">Template:Cite book</ref> It was first patented in 1982<ref name="EngelKleemann2014">Template:Cite book</ref> and was first reported in the scientific literature in June 1987.<ref name="pmid3625091">Template:Cite journal</ref>

Bicalutamide was first studied in a phase I clinical trial in 1987<ref name="Kolvenbag1996" /> and the results of the first phase II clinical trial in prostate cancer were published in 1990.<ref name="pmid2094607">Template:Cite journal</ref> The pharmaceutical division of Template:Abbr 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 Template:Abbr.<ref name="Patents1997">Template:Cite book</ref> It was first launched in the Template:Abbrlink in May 1995,<ref name="ChaurasiyaSingh2012">Template:Cite journal</ref> and was subsequently approved by the Template:Abbr Template:Abbr on 4 October 1995, for the treatment of prostate cancer at a dosage of 50 mg/day in combination with a Template:Abbr analogue.<ref name="Klotz2006">Template:Cite journal</ref><ref name="pmid26236143">Template:Cite journal</ref>

Following its introduction for use in combination with a Template:Abbr 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.<ref name="Wellington2006" /><ref name="Denis2012" /><ref name="pmid11502439">Template:Cite journal</ref><ref name="CarswellFiggitt2002">Template:Cite journal</ref> This application of bicalutamide was also under review by the Template:Abbr in the Template:Abbr in 2002,<ref name="JasminCapanna2005">Template:Cite book</ref> but ultimately was not approved in this country.<ref name="ChabnerLongo2010" /> In Japan, bicalutamide is licensed at a dosage of 80 mg/day alone or in combination with a Template:Abbr analogue for prostate cancer.<ref name="SuzukiKamiya2008"/> 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.<ref name="pmid17199134">Template:Cite journal</ref>

Subsequent to negative findings of bicalutamide monotherapy for Template:Abbr in the Template:Abbr clinical programme, approval of bicalutamide for use specifically in the treatment of Template:Abbr was withdrawn in a number of countries<ref name="pmid18093474">Template:Cite journal</ref> including the Template:Abbr (in October or November 2003)<ref name="BowsherCarter2008">Template:Cite book</ref> and several other European countries and Canada (in August 2003).<ref name="Wellington2006" /><ref name="Nations2005">Template:Cite book</ref><ref name="Bono2004">Template:Cite journal</ref> In addition, the Template:Abbr and Canada explicitly recommended against the use of 150 mg/day bicalutamide for this indication.<ref name="NargundRaghavan2015">Template:Cite book</ref> The drug is effective for, remains approved for, and continues to be used in the treatment of Template:Abbr and Template:Abbr, on the other hand.<ref name="Wellington2006" />

The patent protection of bicalutamide expired in the Template:Abbr in March 2009 and the drug has subsequently been available as a generic,<ref name="Moul2009">Template:Cite journal</ref> at greatly reduced cost.<ref name="Kampel2012">Template:Cite book</ref>

Bicalutamide was the fourth antiandrogen (and the third Template:Abbr) to be introduced for the treatment of prostate cancer, following the Template:Abbr Template:Abbr in 1973<ref name="TobiasHochhauser2014">Template:Cite book</ref> and the Template:Abbr flutamide in 1983 (1989 in the Template:Abbr)<ref name="Publishing2013" /><ref name="Neal1994">Template:Cite book</ref> and nilutamide in 1989 (1996 in the Template:Abbr).<ref name="BéguéBonnet-Delpon2008" /><ref name="Regitz-Zagrosek2012">Template:Cite book</ref><ref name="pmid15833816">Template:Cite journal</ref> 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.<ref name="pmid26585581">Template:Cite journal</ref>

Society and cultureEdit

Generic namesEdit

Bicalutamide is the generic name of the drug in English and French and its Template:Abbrlink, Template:Abbrlink, Template:Abbrlink,<ref name="KEGG">Template:Cite encyclopedia</ref> Template:Abbrlink, Template:Abbrlink, Template:Abbrlink,<ref name="TGALabel" /> and Template:Abbrlink.<ref name="Drugs.com-2" /><ref name="MortonHall2012">Template:Cite book</ref><ref name="IndexNominum2000" /><ref name="GanellinTriggle1996">Template:Cite book</ref> 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.<ref name="Drugs.com-2" /><ref name="IndexNominum2000" /> The "bica-" prefix corresponds to the fact that bicalutamide is a bicyclic compound, while the "-lutamide" suffix is the standard suffix for Template:Abbr.<ref name="WHO2013">Template:Cite report</ref><ref name="NLM-DrugPortal">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Bicalutamide is also known by its former developmental code name Template:Abbr-176,334.<ref name="MortonHall2012" /><ref name="IndexNominum2000" /><ref name="Drugs.com-2" />

Brand namesEdit

Bicalutamide is marketed by AstraZeneca in oral tablet form under the brand names Casodex, Cosudex, Calutide, Calumid, and Kalumid in many countries.<ref name="Drugs.com-2" /><ref name="IndexNominum2000" /><ref name="HuangJo2009">Template:Cite book</ref><ref name="DhasIge2015">Template:Cite journal</ref> It is also marketed under the brand names Bicadex, Bical, Bicalox, Bicamide, Bicatlon, Bicusan, Binabic, Bypro, Calutol, and Ormandyl among others in various countries.<ref name="Drugs.com-2" /> 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.<ref name="Drugs.com-2" /> A combination formulation of bicalutamide and goserelin is marketed by AstraZeneca in Australia and New Zealand under the brand name ZolaCos-CP.<ref name="Martindale2011" /><ref name="Drugs.com-3" /><ref name="ZolacosCPLabelAu" /><ref name="ZolacosCPLabelNZ" />

Cost and genericsEdit

Bicalutamide is off-patent and available as a generic.<ref name="Moul2009"/> Unlike bicalutamide, the newer Template:Abbr enzalutamide is still on-patent, and for this reason, is considerably more expensive in comparison.<ref name="RamadanKabbara2015">Template:Cite journal</ref>

The patent protection of all three of the first-generation Template:Abbr has expired and flutamide and bicalutamide are both available as low-cost generics.<ref name="Stuhan2013">Template:Cite book</ref><ref name="pmid16604181">Template:Cite journal</ref> 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 Template:Abbr<ref name="Stuhan2013" /><ref name="pmid16604181" />

Bicalutamide is considerably less costly than Template:Abbr analogues, which, in spite of some having been off-patent many years, have been reported (in 2013) to typically cost Template:Currency–$15,000 per year (or about Template:Currency per month) of treatment.<ref name="EmansLaufer2012">Template:Cite book</ref><ref name="Hillard2013">Template:Cite book</ref>

Sales and usageEdit

Sales of bicalutamide (as Casodex) worldwide peaked at US$1.3 billion in 2007,<ref name="AstraZeneca2007" /> and it has been described as a "billion-dollar-a-year" drug prior to losing its patent protection starting in 2007.<ref name="Campbell2014" /><ref name="Evaluate2008" /><ref name="pmid16821162">Template:Cite journal</ref> 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).<ref name="Campbell2014" /> Moreover, in spite of being off-patent, bicalutamide was said to still generate a few hundred million dollars in sales per year for AstraZeneca.<ref name="Campbell2014" /> Total worldwide sales of brand name Casodex were approximately US$13.4 billion as of the end of 2018.<ref name="NewMedicine1996" /><ref name="NewYorkTimes1997" /><ref name="AstraZeneca1999" /><ref name="AstraZeneca2001" /><ref name="AstraZeneca2004" /><ref name="AstraZeneca2007" /><ref name="AstraZeneca2010" /><ref name="AstraZeneca2013" /><ref name="AstraZeneca2016" /><ref name="AstraZeneca2017" /><ref name="AstraZeneca2018" />Template:Citation overkill

Worldwide sales (millions, Template:Abbr) 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.<ref name="Evaluate2008">{{#invoke:citation/CS1|citation CitationClass=web

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Between January 2007 and December 2009 (a period of three years), 1,232,143 prescriptions of bicalutamide were dispensed in the Template:Abbr, or about 400,000 prescriptions per year.<ref name="HHS2010" /> During that time, bicalutamide accounted for about 87.2% of the Template:Abbr market, while flutamide accounted for 10.5% of it and nilutamide for 2.3% of it.<ref name="HHS2010" /> Approximately 96% of bicalutamide prescriptions were written for diagnosis codes that clearly indicated neoplasm.<ref name="HHS2010" /> About 1,200, or 0.1% of bicalutamide prescriptions were dispensed to pediatric patients (age 0–16).<ref name="HHS2010" />

RegulationEdit

Bicalutamide is a prescription drug.<ref name="MortonHall2001" /> It is not specifically a controlled substance in any country and therefore is not an illegal drug.<ref name="AHFS2016" /> However, the manufacture, sale, distribution, and possession of prescription drugs are all still subject to legal regulation throughout the world.<ref name="YagielaDowd2010">Template:Cite book</ref><ref name="HeplerSegal2003">Template:Cite book</ref><ref name="DukesDukes1998">Template:Cite book</ref>

ResearchEdit

Bicalutamide has been studied in combination with the 5α-reductase inhibitors finasteride and dutasteride in prostate cancer.<ref name="pmid15138573">Template:Cite journal</ref><ref name="pmid15151957">Template:Cite journal</ref><ref name="pmid16844453">Template:Cite journal</ref><ref name="pmid19796455">Template:Cite journal</ref><ref name="pmid26048455">Template:Cite journal</ref><ref name="pmid26702991">Template:Cite journal</ref><ref name="pmid27330919">Template:Cite journal</ref> It has also been studied in combination with raloxifene, a selective estrogen receptor modulator (SERM), for the treatment of prostate cancer.<ref name="FujimuraTakayama2018">Template:Cite journal</ref><ref name="HoNunez-Nateras2017">Template:Cite journal</ref> Bicalutamide has been tested for the treatment of Template:Abbr-positive Template:Abbr/Template:Abbr-negative locally advanced and metastatic breast cancer in women in a phase II study for this indication.<ref>Template:Cite journal</ref><ref>Template:ClinicalTrialsGov</ref><ref>Template:Cite journal</ref> Enzalutamide is also being investigated for this type of cancer.<ref name="CaiazzaMurray2016">Template:Cite journal</ref><ref>Template:Cite journal</ref> Bicalutamide has also been studied in a phase II clinical trial for ovarian cancer in women.<ref name="pmid17918264">Template:Cite journal</ref>

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.<ref name="Becker2001-2">Template:Cite book</ref><ref name="pmid7694413">Template:Cite journal</ref> Prostate volume decreased by 26% in patients taking bicalutamide and urinary irritative symptom scores significantly decreased.<ref name="Becker2001-2" /><ref name="pmid7694413" /> Conversely, peak urine flow rates and urine pressure flow examinations were not significantly different between bicalutamide and placebo.<ref name="Becker2001-2" /><ref name="pmid7694413" /> 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.<ref name="pmid9101011">Template:Cite journal</ref><ref name="pmid9135028">Template:Cite journal</ref> 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.<ref name="pmid7694413" /><ref name="Kolvenbag1996" />

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 Template:Abbr was completed in Italy in 2017 under supervision of the Italian Agency for Drugs (AIFA).<ref name="pmid29211888">Template:Cite journal</ref>

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.<ref name="pmid32333494">Template:Cite journal</ref><ref name="NCT04374279">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Veterinary useEdit

Bicalutamide may be used to treat hyperandrogenism and associated benign prostatic hyperplasia secondary to hyperadrenocorticism (caused by excessive adrenal androgens) in male ferrets.<ref name = "BonaguraTwedt2013">Template:Cite book</ref><ref name = "MitchellTully2009">Template:Cite book</ref><ref name = "Pilny2014">Template:Cite book</ref> However, it has not been formally assessed in controlled studies for this purpose.<ref name = "Pilny2014" /><ref name = "FoxMarini2014">Template:Cite book</ref>

See alsoEdit

ReferencesEdit

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Further readingEdit

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