羅沙司他

羅沙司他
臨床資料
商品名（英語：Drug nomenclature）	Evrenzo（愛瑞卓）
其他名稱	FG-4592, ASP1517, AZD9941
給藥途徑	口服
ATC碼	B03XA05 (WHO) ;
法律規範狀態
法律規範	中：處方藥 ; 歐：Rx-only; 美：未通過FDA審批; 處方藥（℞-only）;
識別資訊
	IUPAC命名法 2-[(4-Hydroxy-1-methyl-7-phenoxyisoquinoline-3-carbonyl)amino]acetic acid; ;
CAS號	808118-40-3
PubChem CID	11256664;
DrugBank	DB04847;
ChemSpider	9431690;
UNII	X3O30D9YMX;
KEGG	D10593;
CompTox Dashboard（英語：CompTox Chemicals Dashboard） (EPA)	DTXSID60230644 ;
ECHA InfoCard	100.245.356
化學資訊
化學式	C19H16N2O5
摩爾質量	352.35 g·mol−1
3D模型（JSmol（英語：JSmol））	交互式圖像;
	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;

羅沙司他（INN：roxadustat）是一種口服^[1]抗貧血藥，商品名為愛瑞卓（Evrenzo）。屬缺氧誘導因子脯氨酸羥化酶抑制劑，能促進產生內源性紅細胞生成素，以及刺激身體產生紅細胞和血紅蛋白。在臨床試驗階段被作為治療慢性腎病引起的貧血（慢性腎性貧血）藥物而被研究^[2]^[3]。由琺博進（FibroGen, Inc.）和阿斯利康合作開發。

不良反應

羅沙司他常見的副作用有高血壓、在透析相關的血管中形成血栓、腹瀉、外周性水腫（特別是腳踝和腳掌）、高血鉀症和噁心^[1]。

羅沙司他被報導其能導致血管內皮生長因子增加，而血管內皮生長因子是一種能激發腫瘤生長的信號蛋白^[4]。同時被認為能導致肺動脈高壓^[5]。羅沙司他的III期臨床試驗在中華人民共和國內29地開展，期間發現其能引起高血鉀症^[6]。

獲批歷史

2018年12月17日、羅沙司他在中華人民共和國獲得批准用於透析依賴的慢性腎性貧血患者，中國成為羅沙司他第一個獲批的國家^[7]。2019年在日本獲批用於透析依賴的慢性腎性貧血患者，2020年擴大至非透析依賴患者^[8]。2021年7月通過歐盟批准^[1]^[9]。同期7月15日，羅沙司他因副作用問題在美國上市批准遭到FDA拒絕^[10]。

社會與文化

FDA拒絕獲批

2021年7月15日，美國FDA心血管和腎臟藥物諮詢委員會投票反對將羅沙司他用於患有慢性腎病貧血的患者，無論是非透析依賴型患者還是接受透析治療的患者^[11]。委員會專家組針對副作用問題，提出如果不進一步研究，這些問題就無法解決^[12]。值得注意的是，在FDA委員會投票之前，琺博進和阿斯利康宣佈已經改變了用於分析心血管安全數據的參數，這使得該藥物看起來比實際更安全^[13]^[10]。

興奮劑用途

因羅沙司他能促進血紅蛋白水平升高，刺激紅細胞產生的效果成為一種潛在的興奮劑^[14]。因為已經檢測到有運動員非法使用羅沙司他的案例，羅沙司他現被列入表現增強物質篩查名單中^[15]^[16]^[17]。2022年10月美國網球公開賽賽後，西蒙娜·哈勒普被檢測出劑羅沙司他陽性^[18]。2023年9月哈勒普因使用羅沙司他和生物護照異常兩項反興奮劑違規行為被國際網球誠信機構（ITIA）禁賽4年^[14]。但國際體育仲裁法庭在2024年3月將禁賽期縮短至九個月，理由是羅沙司他存在於受污染的補充劑中，並且服用興奮劑並非有意而為^[19]。

參考文獻

^ ^1.0 ^1.1 ^1.2 ^1.3 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.
^ 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.
^ 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 .
^ 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.
^ 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 .
^ 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 .
^ Dhillon S. Roxadustat: First Global Approval. Drugs. April 2019, 79 (5): 563–572. PMID 30805897. S2CID 71147333. doi:10.1007/s40265-019-01077-1 .
^ 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.
^ Evrenzo Product information. Union Register of medicinal products. [3 March 2023].
^ ^10.0 ^10.1 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].
^ FibroGen Announces Outcome of FDA Advisory Committee Review of Roxadustat for Treatment of Anemia of Chronic Kidney Disease. FibroGen (新聞稿). [15 July 2021].
^ Sagonowsky E. AstraZeneca, FibroGen hit another roxadustat setback as FDA panel calls for more safety data. FiercePharma. 15 July 2021 [16 July 2021].
^ 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].
^ ^14.0 ^14.1 Ingle S. Simona Halep given four-year ban from tennis for anti-doping violations. The Guardian. 12 September 2023 [12 September 2023].
^ 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 .
^ 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.
^ 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 .
^ MacInnes P. Simona Halep vows to 'fight for the truth' after positive doping test. The Guardian. 21 October 2022 [21 October 2022].
^ Carayol, Tumaini. Simona Halep's 'triumph of truth' after doping ban significantly reduced. The Guardian. 5 March 2024 [6 March 2024].

[Evrenzo_EPAR-1] 1.0 ^1.1 ^1.2 ^1.3 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].

[FDA-10] 10.0 ^10.1 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 (新聞稿). [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].

[Ingle-14] 14.0 ^14.1 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].

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