罗沙司他

罗沙司他
临床资料
商品名（英语：Drug nomenclature）	Evrenzo（爱瑞卓）
其他名称	FG-4592, ASP1517, AZD9941
给药途径	口服
ATC码	B03XA05 (WHO) ;
法律规范状态
法律规范	中：处方药 ; 欧：Rx-only; 美：未通过FDA审批; 处方药（℞-only）;
识别信息
	IUPAC命名法 2-[(4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid; ;
CAS号	808118-40-3
PubChem CID	11256664;
DrugBank	DB04847;
ChemSpider	9431690;
UNII	X3O30D9YMX;
KEGG	D10593;
CompTox Dashboard（英语：CompTox Chemicals Dashboard） (EPA)	DTXSID60230644 ;
ECHA InfoCard	100.245.356
化学信息
化学式	C19H16N2O5
摩尔质量	352.35 g·mol−1
3D模型（JSmol（英语：JSmol））	交互式图像;
	SMILES CC1=NC(=C(C2=C1C=C(C=C2)OC3=CC=CC=C3)O)C(=O)NCC(=O)O;
	InChI InChI=1S/C19H16N2O5/c1-11-15-9-13(26-12-5-3-2-4-6-12)7-8-14(15)18(24)17(21-11)19(25)20-10-16(22)23/h2-9,24H,10H2,1H3,(H,20,25)(H,22,23); Key:YOZBGTLTNGAVFU-UHFFFAOYSA-N;

罗沙司他（INN：roxadustat）是一种口服^[1]抗贫血药，商品名为爱瑞卓（Evrenzo）。属缺氧诱导因子脯氨酸羟化酶抑制剂，能促进产生内源性红细胞生成素，以及刺激身体产生红细胞和血红蛋白。在临床试验阶段被作为治疗慢性肾病引起的贫血（慢性肾性贫血）药物而被研究^[2]^[3]。由珐博进（FibroGen, Inc.）和阿斯利康合作开发。

Quick Facts 临床资料, 商品名（英语：Drug nomenclature） ...

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不良反应

罗沙司他常见的副作用有高血压、在透析相关的血管中形成血栓、腹泻、外周性水肿（特别是脚踝和脚掌）、高血钾症和恶心^[1]。

罗沙司他被报导其能导致血管内皮生长因子增加，而血管内皮生长因子是一种能激发肿瘤生长的信号蛋白^[4]。同时被认为能导致肺动脉高压^[5]。罗沙司他的III期临床试验在中华人民共和国内29地开展，期间发现其能引起高血钾症^[6]。

获批历史

2018年12月17日、罗沙司他在中华人民共和国获得批准用于透析依赖的慢性肾性贫血患者，中国成为罗沙司他第一个获批的国家^[7]。2019年在日本获批用于透析依赖的慢性肾性贫血患者，2020年扩大至非透析依赖患者^[8]。2021年7月通过欧盟批准^[1]^[9]。同期7月15日，罗沙司他因副作用问题在美国上市批准遭到FDA拒绝^[10]。

社会与文化

FDA拒绝获批

2021年7月15日，美国FDA心血管和肾脏药物咨询委员会投票反对将罗沙司他用于患有慢性肾病贫血的患者，无论是非透析依赖型患者还是接受透析治疗的患者^[11]。委员会专家组针对副作用问题，提出如果不进一步研究，这些问题就无法解决^[12]。值得注意的是，在FDA委员会投票之前，珐博进和阿斯利康宣布已经改变了用于分析心血管安全数据的参数，这使得该药物看起来比实际更安全^[13]^[10]。

兴奋剂用途

因罗沙司他能促进血红蛋白水平升高，刺激红细胞产生的效果成为一种潜在的兴奋剂^[14]。因为已经检测到有运动员非法使用罗沙司他的案例，罗沙司他现被列入表现增强物质筛查名单中^[15]^[16]^[17]。2022年10月美国网球公开赛赛后，西蒙娜·哈勒普被检测出剂罗沙司他阳性^[18]。2023年9月哈勒普因使用罗沙司他和生物护照异常两项反兴奋剂违规行为被国际网球诚信机构（ITIA）禁赛4年^[14]。但国际体育仲裁法庭在2024年3月将禁赛期缩短至九个月，理由是罗沙司他存在于受污染的补充剂中，并且服用兴奋剂并非有意而为^[19]。

参考文献

[1]
Evrenzo EPAR. European Medicines Agency (EMA). 23 June 2021 [24 August 2021]. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
[2]
Provenzano R, Besarab A, Sun CH, Diamond SA, Durham JH, Cangiano JL, Aiello JR, Novak JE, Lee T, Leong R, Roberts BK, Saikali KG, Hemmerich S, Szczech LA, Yu KP, Neff TB. Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD. Clinical Journal of the American Society of Nephrology. June 2016, 11 (6): 982–991. PMC 4891748 . PMID 27094610. doi:10.2215/CJN.06890615.
[3]
Becker K, Saad M. A New Approach to the Management of Anemia in CKD Patients: A Review on Roxadustat. Advances in Therapy. April 2017, 34 (4): 848–853. PMID 28290095. doi:10.1007/s12325-017-0508-9 .
[4]
Zhou M, Hou J, Li Y, Mou S, Wang Z, Horch RE, Sun J, Yuan Q. The pro-angiogenic role of hypoxia inducible factor stabilizer FG-4592 and its application in an in vivo tissue engineering chamber model. Scientific Reports. April 2019, 9 (1): 6035. Bibcode:2019NatSR...9.6035Z. PMC 6465281 . PMID 30988335. doi:10.1038/s41598-019-41924-5.
[5]
Cygulska K, Wejner-Mik P, Plewka M, Figiel Ł, Chrzanowski Ł, Kasprzak JD. Roxadustat: another drug that causes pulmonary hypertension? Report of first human case. Polish Archives of Internal Medicine. May 2019, 129 (5): 344–345. PMID 30758318. doi:10.20452/pamw.4445 .
[6]
Chen N, Hao C, Peng X, Lin H, Yin A, Hao L, Tao Y, Liang X, Liu Z, Xing C, Chen J, Luo L, Zuo L, Liao Y, Liu BC, Leong R, Wang C, Liu C, Neff T, Szczech L, Yu KP. Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis. The New England Journal of Medicine. September 2019, 381 (11): 1001–1010. PMID 31340089. doi:10.1056/NEJMoa1813599 .
[7]
Dhillon S. Roxadustat: First Global Approval. Drugs. April 2019, 79 (5): 563–572. PMID 30805897. S2CID 71147333. doi:10.1007/s40265-019-01077-1 .
[8]
Astellas Receives Approval of Evrenzo (roxadustat) in Japan for the Treatment of Anemia of Chronic Kidney Disease in Adult Patients Not on Dialysis. Astellas. 27 November 2020.
[9]
Evrenzo Product information. Union Register of medicinal products. [3 March 2023].
[10]
Daniel W. Coyne. Roxadustat Use for CKD-Related Anemia Rejected by FDA Advisory Panel. KidneyNews (01 Aug 2021) (American Society of Nephrology). [2024-07-06].
[11]
FibroGen Announces Outcome of FDA Advisory Committee Review of Roxadustat for Treatment of Anemia of Chronic Kidney Disease. FibroGen (新闻稿). [15 July 2021].
[12]
Sagonowsky E. AstraZeneca, FibroGen hit another roxadustat setback as FDA panel calls for more safety data. FiercePharma. 15 July 2021 [16 July 2021].
[13]
Liu A. FibroGen admits to messing with roxadustat safety data, upending hopes for the AZ-partnered anemia drug. Fierce Pharma. 7 April 2021 [30 October 2022].
[14]
Ingle S. Simona Halep given four-year ban from tennis for anti-doping violations. The Guardian. 12 September 2023 [12 September 2023].
[15]
Beuck S, Schänzer W, Thevis M. Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis. Drug Testing and Analysis. November 2012, 4 (11): 830–845. PMID 22362605. doi:10.1002/dta.390 .
[16]
Buisson C, Marchand A, Bailloux I, Lahaussois A, Martin L, Molina A. Detection by LC-MS/MS of HIF stabilizer FG-4592 used as a new doping agent: Investigation on a positive case. Journal of Pharmaceutical and Biomedical Analysis. March 2016, 121: 181–187. PMID 26808067. doi:10.1016/j.jpba.2016.01.029.
[17]
Eichner D, Van Wagoner RM, Brenner M, Chou J, Leigh S, Wright LR, Flippin LA, Martinelli M, Krug O, Schänzer W, Thevis M. lmplementation of the prolyl hydroxylase inhibitor Roxadustat (FG-4592) and its main metabolites into routine doping controls. Drug Testing and Analysis. November 2017, 9 (11–12): 1768–1778. PMID 28378453. doi:10.1002/dta.2202 .
[18]
MacInnes P. Simona Halep vows to 'fight for the truth' after positive doping test. The Guardian. 21 October 2022 [21 October 2022].
[19]
Carayol, Tumaini. Simona Halep's 'triumph of truth' after doping ban significantly reduced. The Guardian. 5 March 2024 [6 March 2024].

[Evrenzo_EPAR-1] [1]
Evrenzo EPAR. European Medicines Agency (EMA). 23 June 2021 [24 August 2021]. Text was copied from this source which is © European Medicines Agency. Reproduction is authorized provided the source is acknowledged.

[2] [2]
Provenzano R, Besarab A, Sun CH, Diamond SA, Durham JH, Cangiano JL, Aiello JR, Novak JE, Lee T, Leong R, Roberts BK, Saikali KG, Hemmerich S, Szczech LA, Yu KP, Neff TB. Oral Hypoxia-Inducible Factor Prolyl Hydroxylase Inhibitor Roxadustat (FG-4592) for the Treatment of Anemia in Patients with CKD. Clinical Journal of the American Society of Nephrology. June 2016, 11 (6): 982–991. PMC 4891748 . PMID 27094610. doi:10.2215/CJN.06890615.

[3] [3]
Becker K, Saad M. A New Approach to the Management of Anemia in CKD Patients: A Review on Roxadustat. Advances in Therapy. April 2017, 34 (4): 848–853. PMID 28290095. doi:10.1007/s12325-017-0508-9 .

[4] [4]
Zhou M, Hou J, Li Y, Mou S, Wang Z, Horch RE, Sun J, Yuan Q. The pro-angiogenic role of hypoxia inducible factor stabilizer FG-4592 and its application in an in vivo tissue engineering chamber model. Scientific Reports. April 2019, 9 (1): 6035. Bibcode:2019NatSR...9.6035Z. PMC 6465281 . PMID 30988335. doi:10.1038/s41598-019-41924-5.

[5] [5]
Cygulska K, Wejner-Mik P, Plewka M, Figiel Ł, Chrzanowski Ł, Kasprzak JD. Roxadustat: another drug that causes pulmonary hypertension? Report of first human case. Polish Archives of Internal Medicine. May 2019, 129 (5): 344–345. PMID 30758318. doi:10.20452/pamw.4445 .

[6] [6]
Chen N, Hao C, Peng X, Lin H, Yin A, Hao L, Tao Y, Liang X, Liu Z, Xing C, Chen J, Luo L, Zuo L, Liao Y, Liu BC, Leong R, Wang C, Liu C, Neff T, Szczech L, Yu KP. Roxadustat for Anemia in Patients with Kidney Disease Not Receiving Dialysis. The New England Journal of Medicine. September 2019, 381 (11): 1001–1010. PMID 31340089. doi:10.1056/NEJMoa1813599 .

[7] [7]
Dhillon S. Roxadustat: First Global Approval. Drugs. April 2019, 79 (5): 563–572. PMID 30805897. S2CID 71147333. doi:10.1007/s40265-019-01077-1 .

[8] [8]
Astellas Receives Approval of Evrenzo (roxadustat) in Japan for the Treatment of Anemia of Chronic Kidney Disease in Adult Patients Not on Dialysis. Astellas. 27 November 2020.

[9] [9]
Evrenzo Product information. Union Register of medicinal products. [3 March 2023].

[FDA-10] [10]
Daniel W. Coyne. Roxadustat Use for CKD-Related Anemia Rejected by FDA Advisory Panel. KidneyNews (01 Aug 2021) (American Society of Nephrology). [2024-07-06].

[11] [11]
FibroGen Announces Outcome of FDA Advisory Committee Review of Roxadustat for Treatment of Anemia of Chronic Kidney Disease. FibroGen (新闻稿). [15 July 2021].

[12] [12]
Sagonowsky E. AstraZeneca, FibroGen hit another roxadustat setback as FDA panel calls for more safety data. FiercePharma. 15 July 2021 [16 July 2021].

[13] [13]
Liu A. FibroGen admits to messing with roxadustat safety data, upending hopes for the AZ-partnered anemia drug. Fierce Pharma. 7 April 2021 [30 October 2022].

[Ingle-14] [14]
Ingle S. Simona Halep given four-year ban from tennis for anti-doping violations. The Guardian. 12 September 2023 [12 September 2023].

[15] [15]
Beuck S, Schänzer W, Thevis M. Hypoxia-inducible factor stabilizers and other small-molecule erythropoiesis-stimulating agents in current and preventive doping analysis. Drug Testing and Analysis. November 2012, 4 (11): 830–845. PMID 22362605. doi:10.1002/dta.390 .

[16] [16]
Buisson C, Marchand A, Bailloux I, Lahaussois A, Martin L, Molina A. Detection by LC-MS/MS of HIF stabilizer FG-4592 used as a new doping agent: Investigation on a positive case. Journal of Pharmaceutical and Biomedical Analysis. March 2016, 121: 181–187. PMID 26808067. doi:10.1016/j.jpba.2016.01.029.

[17] [17]
Eichner D, Van Wagoner RM, Brenner M, Chou J, Leigh S, Wright LR, Flippin LA, Martinelli M, Krug O, Schänzer W, Thevis M. lmplementation of the prolyl hydroxylase inhibitor Roxadustat (FG-4592) and its main metabolites into routine doping controls. Drug Testing and Analysis. November 2017, 9 (11–12): 1768–1778. PMID 28378453. doi:10.1002/dta.2202 .

[18] [18]
MacInnes P. Simona Halep vows to 'fight for the truth' after positive doping test. The Guardian. 21 October 2022 [21 October 2022].

[19] [19]
Carayol, Tumaini. Simona Halep's 'triumph of truth' after doping ban significantly reduced. The Guardian. 5 March 2024 [6 March 2024].

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