首个获批FXa抑制剂特异性拮抗剂andexanet alfa
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摘要
andexanet alfa是一种重组的凝血因子Xa(FXa)诱导蛋白,是FXa抑制剂的竞争性拮抗剂。2018年5月3日获FDA批准andexanet alfa用于治疗与利伐沙班及阿哌沙班相关的危及生命或无控制出血后的抗凝逆转。andexanet alfa在FXa结构基础上修饰而获得,与FXa抑制剂具有相同的亲和力而无任何抗凝血活性和促凝血活性。作为首个且唯一FXa抑制剂的特异性拮抗剂,andexanet alfa获得FDA加速批准同时获得突破性疗法及孤儿药资格认定。本文对andexanet alfa的生化特性、临床药理学、临床评价和安全性等进行综述。
Andexanet alfa is a recombinant modified human Factor Xa(FXa) protein,which is a competitive antagonist of FXa inhibitors. On May 3,2018,andexanet alfa was approved by FDA for the patients treated with rivaroxaban and apixaban,when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. Andexanet alfa is a recombinant modified FXa decoy protein that is catalytically inactive but that retains the ability to bind FXa at the active site with high affinity. As the first and only specific inhibitor of FXa,andexanet alfa was approved under accelerated approval and obtained breakthrough therapy and orphan drug qualification by FDA. This review presents the biochemical characteristics,clinical pharmacology,clinical evaluation and safety of andexanet alfa.
Andexanet alfa is a recombinant modified human Factor Xa(FXa) protein,which is a competitive antagonist of FXa inhibitors. On May 3,2018,andexanet alfa was approved by FDA for the patients treated with rivaroxaban and apixaban,when reversal of anticoagulation is needed due to life-threatening or uncontrolled bleeding. Andexanet alfa is a recombinant modified FXa decoy protein that is catalytically inactive but that retains the ability to bind FXa at the active site with high affinity. As the first and only specific inhibitor of FXa,andexanet alfa was approved under accelerated approval and obtained breakthrough therapy and orphan drug qualification by FDA. This review presents the biochemical characteristics,clinical pharmacology,clinical evaluation and safety of andexanet alfa.
引文
[1]PINTO DJ,SMALLHEEL JM,CHENEY DL,et al.Factor Xa Inhibitors:next-Generation Antithrombotic Agents[J].J Med Chem,2010,53(17):6243-6274.
[2]SUN D,LAZOLANGER A.New oral anticoagulants[J].JThromb Thrombol,2011,31(3):310-320.
[3]薛蒙,周建中.新型口服抗凝药特异性拮抗剂研究进展[J].药学与临床研究,2017,25(3):227-231.
[4]SCOOT P,RICHARD T,MARK R.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[J].N Engl J Med,2011,365(10):883.
[5]GIUGLIANO RP,RUFF CT,BRAUNWALD E,et al.Edoxaban versus warfarin in patients with atrial fibrillation[J].N Engl JMed,2013,369(22):2093-2104.
[6]GRANGER CB,ALEXANDER JH,MC JJ,et al.Apixaban versus warfarin in patients with atrial fibrillation[J].N Engl JMed,2011,365(11):981-992.
[7]BEYER-WESTENDORF J,FORDDTER K,PANNACH S,et al.Rates,management and outcome of bleeding complications during rivaroxaban therapy in daily care:results from the Dresden NOACregistry[J].Blood,2014,124(6):955-962.
[8]TAMAYO S,FRANK W,PATEL M,et al.Characterizing major bleeding in patients with nonvalvular atrial fibrillation:a pharmacovigilance study of 27467 patients taking rivaroxaban[J].Clin Cardiol,2015,38(2):63-68.
[9]HELD C,HYLEK EM,ALEXANDER JH,et al.Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin:insights from the ARISTOTLE trial[J].Eur Heart J,2015,36(20):1264-1272.
[10]ANSELL JE,BAKHRU SH,LAULICHT BE,et al.Use of PER977 to reverse the anticoagulant effect of edoxaban-NEJM[J].N Engl J Med,2014,371(22):2141-2142.
[11]ANSELL JE,BAKHRU SH,LAULICHT BE,et al.Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban[J].Thrombosis Haemostasis,2016,117(2):238-245.
[12]GOLDIN M,HUGHES J,CHOUDHARY Z,et al.Reversal of anticoagulation:therapeutic advances and clinical guidelines[J].Am J Therapeut,2018,25(1):e44-e52.
[13]GHADIMI K,DOMBROWSKI KE,LEVY JH,et al.Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation[J].Expert Rev Hematol,2016,9(2):115-122.
[14]LU G,GUZMAN FR,HOLLENBACH SJ,et al.A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa[J].Nat Med,2013,19(4):446-451.
[15]邱小妙,张蕊,郝春华,等.FXa抑制剂特异性拮抗剂Andexanet alfa的研究进展[J].山东医药,2018,58(12):105-108.
[16]SIEGAL D,LU G,LEEDS JM,et al.Safety,pharmacokinetics,and reversal of apixaban anticoagulation with andexanet alfa[J].Blood Adv,2017,21(1):1827-1838.
[17]KAATZ S,BHANSALI H,GIBBS J,et al.Reversing factor Xa inhibitors-clinical utility of andexanet alfa[J].J Blood Med,2017,8:141-149.
[18]Portola Pharmaceuticals,Inc.Andexxa-prescribing-information[EB/OL].[2018-06-12].https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm606681.htm.
[19]CROWHHER M,KITT M,CLURE M,et al.Abstract 10:randomized,double-blind,placebo-controlled single ascending dose pharmacokinetic and pharmacodynamic study of PRT064445,a universal antidote for Factor Xa inhibitors[J].Arteriosclerosis Thromb Vascular Biol,2013,33(Suppl 1):A10.
[20]VINCENTI F,FERVENZA FC,CAMPBEL KN,et al.A phase 2,double-blind,placebo-controlled,randomized study of fresolimumab in patients with steroid-resistant primary focal segmental glomerulosclerosis[J].Kidney Int Rep,2017,2(5):800-810.
[21]SIEGAL DM,CURNUTTE JT,CONNOLLY SJ,et al.Andexanet alfa for the reversal of factor Xa inhibitor activity[J].N Engl J Med,2015,373(25):2413-2424.
[22]LU G,PINE P,LEEDS JM,et al.Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model[J].Plos One,2018,13(3):e0195122
[23]SARTORI M,COSMI B.Andexanet alfa to reverse the anticoagulant activity of factor Xa inhibitors:a review of design,development and potential place in therapy[J].J Thromb Thrombol,2018,45(11):1-8.
[24]CONNOLLY SJ,GIBISON CM,CROWTHER M.Andexanet Alfa for factor Xa inhibitor reversal[J].N Engl J Med,2016,375(25):2499-2500.
[2]SUN D,LAZOLANGER A.New oral anticoagulants[J].JThromb Thrombol,2011,31(3):310-320.
[3]薛蒙,周建中.新型口服抗凝药特异性拮抗剂研究进展[J].药学与临床研究,2017,25(3):227-231.
[4]SCOOT P,RICHARD T,MARK R.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation[J].N Engl J Med,2011,365(10):883.
[5]GIUGLIANO RP,RUFF CT,BRAUNWALD E,et al.Edoxaban versus warfarin in patients with atrial fibrillation[J].N Engl JMed,2013,369(22):2093-2104.
[6]GRANGER CB,ALEXANDER JH,MC JJ,et al.Apixaban versus warfarin in patients with atrial fibrillation[J].N Engl JMed,2011,365(11):981-992.
[7]BEYER-WESTENDORF J,FORDDTER K,PANNACH S,et al.Rates,management and outcome of bleeding complications during rivaroxaban therapy in daily care:results from the Dresden NOACregistry[J].Blood,2014,124(6):955-962.
[8]TAMAYO S,FRANK W,PATEL M,et al.Characterizing major bleeding in patients with nonvalvular atrial fibrillation:a pharmacovigilance study of 27467 patients taking rivaroxaban[J].Clin Cardiol,2015,38(2):63-68.
[9]HELD C,HYLEK EM,ALEXANDER JH,et al.Clinical outcomes and management associated with major bleeding in patients with atrial fibrillation treated with apixaban or warfarin:insights from the ARISTOTLE trial[J].Eur Heart J,2015,36(20):1264-1272.
[10]ANSELL JE,BAKHRU SH,LAULICHT BE,et al.Use of PER977 to reverse the anticoagulant effect of edoxaban-NEJM[J].N Engl J Med,2014,371(22):2141-2142.
[11]ANSELL JE,BAKHRU SH,LAULICHT BE,et al.Single-dose ciraparantag safely and completely reverses anticoagulant effects of edoxaban[J].Thrombosis Haemostasis,2016,117(2):238-245.
[12]GOLDIN M,HUGHES J,CHOUDHARY Z,et al.Reversal of anticoagulation:therapeutic advances and clinical guidelines[J].Am J Therapeut,2018,25(1):e44-e52.
[13]GHADIMI K,DOMBROWSKI KE,LEVY JH,et al.Andexanet alfa for the reversal of Factor Xa inhibitor related anticoagulation[J].Expert Rev Hematol,2016,9(2):115-122.
[14]LU G,GUZMAN FR,HOLLENBACH SJ,et al.A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa[J].Nat Med,2013,19(4):446-451.
[15]邱小妙,张蕊,郝春华,等.FXa抑制剂特异性拮抗剂Andexanet alfa的研究进展[J].山东医药,2018,58(12):105-108.
[16]SIEGAL D,LU G,LEEDS JM,et al.Safety,pharmacokinetics,and reversal of apixaban anticoagulation with andexanet alfa[J].Blood Adv,2017,21(1):1827-1838.
[17]KAATZ S,BHANSALI H,GIBBS J,et al.Reversing factor Xa inhibitors-clinical utility of andexanet alfa[J].J Blood Med,2017,8:141-149.
[18]Portola Pharmaceuticals,Inc.Andexxa-prescribing-information[EB/OL].[2018-06-12].https://www.fda.gov/biologicsbloodvaccines/cellulargenetherapyproducts/approvedproducts/ucm606681.htm.
[19]CROWHHER M,KITT M,CLURE M,et al.Abstract 10:randomized,double-blind,placebo-controlled single ascending dose pharmacokinetic and pharmacodynamic study of PRT064445,a universal antidote for Factor Xa inhibitors[J].Arteriosclerosis Thromb Vascular Biol,2013,33(Suppl 1):A10.
[20]VINCENTI F,FERVENZA FC,CAMPBEL KN,et al.A phase 2,double-blind,placebo-controlled,randomized study of fresolimumab in patients with steroid-resistant primary focal segmental glomerulosclerosis[J].Kidney Int Rep,2017,2(5):800-810.
[21]SIEGAL DM,CURNUTTE JT,CONNOLLY SJ,et al.Andexanet alfa for the reversal of factor Xa inhibitor activity[J].N Engl J Med,2015,373(25):2413-2424.
[22]LU G,PINE P,LEEDS JM,et al.Andexanet alfa effectively reverses edoxaban anticoagulation effects and associated bleeding in a rabbit acute hemorrhage model[J].Plos One,2018,13(3):e0195122
[23]SARTORI M,COSMI B.Andexanet alfa to reverse the anticoagulant activity of factor Xa inhibitors:a review of design,development and potential place in therapy[J].J Thromb Thrombol,2018,45(11):1-8.
[24]CONNOLLY SJ,GIBISON CM,CROWTHER M.Andexanet Alfa for factor Xa inhibitor reversal[J].N Engl J Med,2016,375(25):2499-2500.