比卡鲁胺

比卡鲁胺（英语：Bicalutamide）以Casodex（康士得）等品牌于市面销售，是种抗雄激素药物，主要用于治疗摄护腺癌。^[10]它通常与促性腺激素释放激素调节剂（英语：gonadotropin-releasing hormone） (GnRH) 类似物或睾丸切除术（去势）同时使用，以治疗转移性摄护腺癌 (mPC)。^[11][10][12]在较不严重的案例，可用它作单一疗法，以高剂量治疗局部晚期摄护腺癌（LAPC），而无需进行去势。^[4][2][13]比卡鲁胺曾被用作治疗局限性摄护腺癌 (LPC) 的单一疗法，但因临床试验结果不佳，核准遭到撤销。比卡鲁胺除用于治疗摄护腺癌之外，也被有限地用于治疗女性先天性遗传多毛症和雄激素性脱发，^[14][15]并用于处理男性阴茎异常勃起。^[16]此药物系透过口服方式给药。^[10]

比卡鲁胺

临床数据
读音	Bicalutamide: • /ˌbaɪkəˈluːtəmaɪd/[1] • BY-kə-LOO-tə-myde[1]
商品名（英语：Drug nomenclature）	Casodex、Calutex及其他
其他名称	ICI-176,334，ZD-176,334
AHFS/Drugs.com	Monograph
MedlinePlus	a697047
核准状况	美 DailyMed: Bicalutamide
怀孕分级	澳: D
给药途径	口服给药[2]
药物类别（英语：Drug class）	非类固醇抗雄激素（英语：nonsteroidal antiandrogen）
ATC码	L02BB03 (WHO)
法律规范状态
法律规范	澳：限医生处方（S4） 英：处方药（℞-only） (POM) 美：处方药（℞-only） 处方药（℞-only）
药物动力学数据
生物利用度	容易吸收，绝对生物利用度尚未知[3]
血浆蛋白结合率	外消旋体: 96.1%[2] 对映异构: 99.6%[2] (主要与人类血清白蛋白（英语：human serum albumin）结合)[2]
药物代谢	肝脏 (广泛性):[4][9] • 羟基化 (CYP3A4) • 葡糖苷酸化（英语：Glucuronidation） (UGT1A9（英语：UGT1A9）酶)
代谢产物	• 比卡鲁胺葡糖苷酸 •羟基比卡鲁胺 • 羟基比卡鲁胺 葡糖苷酸 (全部非活性)[4][2][5][6]
生物半衰期	单剂量: 5.8天[7] 持续使用: 7–10天[8]
排泄途径	粪便: 43%[4] 尿液: 34%[4]
识别信息
IUPAC命名法 (RS)-N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methylpropanamide
CAS号	90357-06-5（ 113299-40-4 ((R)-isomer) 113299-38-0 ((S)-isomer)）  Y
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配体ID	198 (PDBe, RCSB PDB)
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID2022678
ECHA InfoCard	100.126.100
化学信息
化学式	C18H14F4N2O4S
摩尔质量	430.37 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像
手性	外消旋体 (of (R)- and (S)-对映异构)
熔点	191至193 °C（376至379 °F） (实验性)
沸点	650 °C（1,202 °F） (推测)
水溶性	0.005
SMILES CC(O)(CS(=O)(=O)c1ccc(F)cc1)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
InChI 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

使用后对男性的常见副作用有男性乳腺发育、乳房疼痛和潮热。^[10]对男性的其他副作用有女性化和性功能障碍。^[17][18]如进行过去势手术，有些副作用（例如乳腺发育和女性化）会大幅减少。^[19]虽然该药物对女性产生的副作用似乎很少，但目前美国食品药物管理局 (FDA) 尚未明确批准提供女性使用。^[20][10]个体于怀孕期间使用此药物可能会伤害胎儿。^[10]在罹患早期摄护腺癌的男性中，使用比卡鲁胺单一疗法会增加摄护腺癌以外原因导致死亡的可能性。^[21][13]比卡鲁胺会导致约1%的使用者出现异常肝脏变化（转氨酶升高（英语：elevated transaminases））而须停止用药。^[22][13]罕见的情况有与严重肝损伤、^[10]严重肺毒性（英语：Pulmonary toxicity）、^[3]和对光敏感的案例有关联。^[23][24]虽然肝脏发生不良变化的风险很小，仍建议在治疗期间进行肝功能检测。^[10]

比卡鲁胺是种非类固醇抗雄激素（英语：nonsteroidal antiandrogen） (NSAA) 类药物。^[3]它透过选择性阻断雄激素受体 (AR) 而发挥作用。^[25]人体对比卡鲁胺的吸收度良好，饮食期间服用并不受影响。^[2]药物的生物半衰期约为一周。^[2][10]它在动物体内是种周边选择性药物（英语：Peripherally selective drug），但对人类而言，则会穿过血脑屏障并对身体和大脑产生影响。^[2][26]

比卡鲁胺于1982年取得专利，于1995年获准用于医疗用途，^[27]并已被列入世界卫生组织基本药物标准清单中。^[28]市面已有通用名药物贩售。^[29]该药物在80多个国家（包括大多数发达国家）流通。^[30][31][32]

医疗用途

主条目：比卡鲁胺医疗用途（英语：medical uses of bicalutamide）

比卡鲁胺主要用于以下适应症：^[33]

• 男性转移性摄护腺癌 (mPC) ，同时摄取促性腺激素释放激素调节剂 (GnRH) 类似物或是与去势手术联合使用，每日摄取50毫克。^[22][4][34]
• 男性局部晚期摄护腺癌 (LAPC) 单一疗法，每日摄取150毫克（美国并未批准此种用途）^{[4][2][13][35]}

日本核准的治疗摄护腺癌，药物使用剂量为每日80毫克，既可与去势手术结合使用，也可作单一疗法使用。^[36][37]

比卡鲁胺的仿单标示外使用适应症有：

• 减少男性接受GnRH激动剂治疗开始时睾酮激增的影响。^[38][39]
• 雄激素依赖性（英语：androgen-dependent condition）皮肤和毛发疾病，如女性痤疮、皮脂分泌旺盛、先天性遗传多毛症和雄激素性脱发，以及女性多囊卵巢综合症 (PCOS) 导致的高睾酮水平，通常会与避孕药联合使用，比卡鲁胺的用量为每日25至50毫克。^{[14][40][41][42][43][44][45]}
• 为跨性别女性进行女性化激素疗法，通常与雌激素合并使用，剂量为每日50毫克。^{[46][47][48][49][50][51][52]}
• 男孩周边性早熟（特别是家族性男性限定性性早熟（英语：Familial male-limited precocious puberty）（睾丸毒性），每日服用12.5至100毫克，与芳香化酶抑制剂（英语：Aromatase inhibitor）（如阿那曲唑）联合使用。^{[22][53][54][55][56][57][58]}
• 男性阴茎异常勃起，每周摄取50毫克至每隔一天摄取50毫克。^{[59][60][61][62][3][7][16]}

此药物已被建议用于以下适应症，但效果尚不确定：

• 性欲亢进和性偏离，特别是与化学阉割结合使用。^{[63][64][65][66][67][68]}

配方形式

比卡鲁胺在全球80多个国家（大多数为发达国家）经核准用于治疗摄护腺癌。^{[69][30][70][31][32]}有50毫克、80毫克（在日本）^[36]和150毫克口服片剂形式。该药物在至少55个国家注册为每日150毫克的单一疗法，以治疗男性局部晚期摄护腺癌，^[2]但在美国是一明显例外，该药物仅注册为每日50毫克的剂量，结合去势使用。^[71]

禁忌症

比卡鲁胺在美国属于妊娠X类，即"妊娠禁忌"，^[22]在"澳大利亚"属于妊娠D类，即第二大限制级别。^[72]因此怀孕期间的女性禁用比卡鲁胺，强烈建议性活跃且能够或可能怀孕的女性仅在采取适当避孕措施的情况下才能服用比卡鲁胺。^[73][74]目前尚不清楚比卡鲁胺是否会进入母乳中，但同样不建议在个体进行母乳哺育时使用比卡鲁胺。^[3][22]

对患有严重肝病的个体，有证据显示人体消除比卡鲁胺的速度会减慢，由于体内比卡鲁胺的水平可能会因此增加，患者需要谨慎。^[2][75]比卡鲁胺的生物半衰期在肾功能损害患者体中并无变化。^[71]

副作用

主条目：比卡鲁胺副作用（英语：side effects of bicalutamide）

比卡鲁胺的副作用很大程度上取决于性别。在男性中，由于雄激素缺乏症（英语：Androgen deficiency），有不同严重程度的副作用会出现，最常见的是乳房疼痛/压痛和乳腺发育。 在接受比卡鲁胺单一药物治疗的男性中，高达80%的男性会出现乳腺发育，超过90%的乳腺发育的严重程度为轻度至中度。^[76][77]其他与雄性素缺乏类似的副作用有潮热、性功能障碍（例如性冲动丧失、勃起功能障碍）、忧郁、疲劳、虚弱和贫血。^[78][79][80]

比卡鲁胺与肝功能检查异常结果（例如肝脏酵素水平升高）有关联。^[79][13]建议在治疗期间监测肝功能，特别是在最初的几个月。^[13][78]在患有早期摄护腺癌的男性中，发现使用比卡鲁胺单一疗法会增加非摄护腺癌原因的死亡率。^[21][81][13]这些死亡率增加的原因尚不清楚，可能的因素包括雄激素缺乏或比卡鲁胺药物相关毒性。^[82][83]

截至2022年，已有10例与比卡鲁胺相关的肝毒性病例报告提出。^{[84][85][86][87]}

由于比卡鲁胺是一种抗雄激素，理论上存在导致男性胎儿先天性障碍的风险，例如生殖器不明确。^{[73][74][88][89]}由于这种可能的致畸能力，具有生育能力和性活跃的女性于服用比卡鲁胺时，应采取避孕措施。^[90]

过量

尚未确定人类单次摄取比卡鲁胺会导致过量症状，或被认为会危及生命。^[22][91]在临床试验中，高达每日600毫克的剂量仍受到良好耐受。^[92]

与其他药物交互作用

比卡鲁胺几乎完全由肝脏的CYP3A4代谢。^[4]因此CYP3A4的抑制剂和诱导剂可能会改变药物在体内的水平。^[7]虽然比卡鲁胺是由CYP3A4代谢，但没证据显示使用剂量为每日150毫克或更少，而同时使用其他引发或抑制CYP3A4的药物后会发生临床上显著的药物交互作用。^[13]

由于比卡鲁胺以相对较高的浓度在人体中循环，且具有高度蛋白质结合力，因此有可能取代血浆中华法林、苯妥英、茶碱和阿司匹林等其他具高度蛋白质结合力的药物。^[76][79]

药理学

药效学

主条目：比卡鲁胺药理作用#药效学（英语：Pharmacology of bicalutamide#Pharmacodynamics）

药物动力学

主条目：比卡鲁胺药理作用#药物动力学（英语：Pharmacology of bicalutamide#Pharmacokinetics）

此药物在人体中的绝对生物利用度尚未被完全了解，^[2][3]但已知比卡鲁胺具有广泛且吸收良好的特性。其吸收不受患者进行饮食的影响。^[3][93]

比卡鲁胺的药物动力学不受同时进食、年龄或体重、肾功能损害或轻至中度肝功能损害的影响。^[2][94]然而服用此药物的日本人，其体内药物的稳态水准会高于白人的。^[2]

化学性质

类似物

参见：抗雄激素的发现与开发（英语：Discovery and development of antiandrogens）

第一代非类固醇抗雄激素药物包括比卡鲁胺、氟他胺和尼鲁米特（英语：nilutamide），都是合成的非类固醇苯胺（抗雄激素）衍生物，并且彼此具有类似结构。^[95]

合成

已有许多文献提出比卡鲁胺的化学合成法。^{[96][97][98][99][100]}首次发表的比卡鲁胺的合成过程如下图所示。^[97]

Bicalutamide synthesis[97] 起始原料为4-氰基-3-(三氟甲基)苯胺4-cyano-3-(trifluoromethyl)aniline（英语：4-氰基-3-(三氟甲基)苯胺4-cyano-3-(trifluoromethyl)aniline）（另称4-氨基-2-(三氟甲基)苯腈（4-amino-2-(trifluoromethyl)benzonitrile）），DMA为二甲基乙酰胺简称，mCPBA为间氯过氧苯甲酸简称。

历史

比卡鲁胺以及目前上市的所有非类固醇抗雄激素药物均源自氟他胺的结构修饰，氟他胺本身最初于1967年由先灵葆雅公司合成，作抑菌剂用途，而后偶然发现其具有抗雄激素活性。^{[101][102][103]}比卡鲁胺由在帝国化学工业 (ICI) 工作的Tucker及其同事于20世纪80年代从超过2,000种合成化合物筛选后开发而成。^{[104][105][106][96]}此化合物于1982年首次获得专利，^[107]并于1987年6月首次在科学文献中提出报告。^[108]

比卡鲁胺为通用名称，在各种国际性及国家性药典/名称登记中均被使用。^{[109][72][30][110][69][111]}

社会与文化

品牌名称

有Casodex、Cosudex、Calutide、Calumid和Kalumi等。^{[30][69][112][113]}

通用名药物

比卡鲁胺已不受专利保护，市面有众多通用名药物流通，^[114]而且价格较为便宜。^[115][116]

销售

比卡鲁胺（如Casodex）的全球销售额于2007年达到13亿美元的峰值，^[117]在2007年失去专利保护之前，它是种"每年销售达十亿美元"的药物之一。^{[118][119][120]}比卡鲁胺仍然是转移性摄护腺癌经去势手术后最常用的处方药。^[118]

于2007年到2009的两年间，在美国开立的NSAA处方笺中，比卡鲁胺约占87.2%，氟他胺占10.5%，尼鲁米特占2.3%。^[121]

研究

目前有将比卡鲁胺与5α-还原酶抑制剂（英语：5α-reductase inhibitors）非那雄胺和度他雄胺（英语：dutasteride）联合，以治疗摄护腺癌的研究。^{[122][123][124][125][126][127][128]}它也与雷洛昔芬（一种选择性雌激素受体调节物（SERM））联合用于治疗摄护腺癌。^[129][130]

有使用抗雄激素药物治疗男性COVID-19的提议，截至2020年5月，使用高剂量比卡鲁胺的疗法正处于II期临床试验中。^[131][132]

参见

• 比卡鲁胺与其他抗雄激素的比较（英语：Comparison of bicalutamide with other antiandrogens）

参考文献

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16. Yuan J, Desouza R, Westney OL, Wang R. Insights of priapism mechanism and rationale treatment for recurrent priapism. Asian Journal of Andrology. 2008, 10 (1): 88–101. PMID 18087648. doi:10.1111/j.1745-7262.2008.00314.x .
17. Elliott S, Latini DM, Walker LM, Wassersug R, Robinson JW. Androgen deprivation therapy for prostate cancer: recommendations to improve patient and partner quality of life. The Journal of Sexual Medicine. 2010, 7 (9): 2996–3010. PMID 20626600. doi:10.1111/j.1743-6109.2010.01902.x.
18. Hammerer P, Manka L. Androgen Deprivation Therapy for Advanced Prostate Cancer. Urologic Oncology. Springer International Publishing. 2019: 255–276. ISBN 978-3-319-42622-8. doi:10.1007/978-3-319-42623-5_77. 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).
19. Droz J, Audisio RA. Management of Urological Cancers in Older People. Springer Science & Business Media. 2012-10-02: 84–. ISBN 978-0-85729-986-4. （原始内容存档于2016-05-11）.
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21. Jia AY, Spratt DE. Bicalutamide Monotherapy With Radiation Therapy for Localized Prostate Cancer: A Non-Evidence-Based Alternative. Int J Radiat Oncol Biol Phys. June 2022, 113 (2): 316–319. PMID 35569476. S2CID 248765294. doi:10.1016/j.ijrobp.2022.01.037. 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 >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.
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37. Usami M, Akaza H, Arai Y, Hirano Y, Kagawa S, Kanetake H, Naito S, Sumiyoshi Y, Takimoto Y, Terai A, Yoshida H, Ohashi Y. 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. 2007, 10 (2): 194–201. PMID 17199134. doi:10.1038/sj.pcan.4500934 . 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.
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延伸阅读

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