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Abstract：
BACKGROUND: Prophylaxis with either intravenous (i.v.) factor VIII (FVIII) or FIX is the gold standard of care for patients with severe hemophilia. A monoclonal antibody (concizumab) targeting tissue factor pathway inhibitor (TFPI) that can be administered subcutaneously (s.c.) has the potential to alter current concepts of prophylaxis in hemophilia.
OBJECTIVE: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B.
METHODS: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 μg kg(-1) ) or s.c. (50-3000 μg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24).
RESULTS: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h μg mL(-1) and a maximum mean concentration of 247 μg mL(-1) was measured at the highest dose.
CONCLUSIONS: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment.
OBJECTIVE: To evaluate the safety and describe the pharmacokinetics and pharmacodynamics of single-dose concizumab in healthy volunteers and patients with hemophilia A or B.
METHODS: In this first human dose, phase 1, multicenter, randomized, double-blind, placebo-controlled trial escalating single i.v. (0.5-9000 μg kg(-1) ) or s.c. (50-3000 μg kg(-1) ) doses of concizumab were administered to healthy volunteers (n = 28) and hemophilia patients (n = 24).
RESULTS: Concizumab had a favorable safety profile after single i.v. or s.c. administration. There were no serious adverse events and no anti-concizumab antibodies. No clinically relevant changes in platelets, prothrombin time, activated partial thromboplastin time, fibrinogen, or antithrombin were found. A dose-dependent procoagulant effect of concizumab was seen as increased levels of D-dimers and prothrombin fragment 1 + 2. Nonlinear pharmacokinetics of concizumab was observed due to target-mediated clearance. A maximum mean AUC0-∞ of 33 960 h μg mL(-1) and a maximum mean concentration of 247 μg mL(-1) was measured at the highest dose.
CONCLUSIONS: Concizumab showed a favorable safety profile after i.v. or s.c. administration and nonlinear pharmacokinetics was observed due to target-mediated clearance. A concentration-dependent procoagulant effect of concizumab was observed, supporting further study into the potential use of s.c. concizumab for hemophilia treatment.
摘要：
背景：静脉内（i.v.）因子VIII（FVIII）或FIX的预防是治疗严重血友病患者的黄金标准。可以皮下(s.c.)施用的靶向组织因子途径抑制剂(TFPI)的单克隆抗体(concizumab)具有改变当前血友病预防概念的潜力。
目的：为了评估单剂量康西单抗在健康志愿者和血友病A或B患者中的安全性并描述其药代动力学和药效学。
方法：在第一个人剂量中，第一阶段，多中心，随机化，双盲,安慰剂对照试验对健康志愿者(n=28)和血友病患者(n=24)给予单次静脉内(0.5-9000μgkg(-1))或皮下(50-3000μgkg(-1))剂量的康西珠单抗.
结果：康西单抗在单次静脉或皮下给药后具有良好的安全性。没有严重不良事件，也没有抗康单抗抗体。血小板无临床相关变化,凝血酶原时间,活化部分凝血活酶时间，纤维蛋白原，或者发现了抗凝血酶.康西单抗的剂量依赖性促凝血作用被视为D-二聚体和凝血酶原片段1+2的水平增加。由于靶标介导的清除，观察到了康西单抗的非线性药代动力学。在最高剂量下测量的最大平均AUC0-∞为33.960hμgmL(-1)和最大平均浓度为247μgmL(-1)。
结论：康西单抗在静脉或皮下给药后显示出良好的安全性，并且由于靶标介导的清除而观察到非线性药代动力学。观察到康西珠单抗的浓度依赖性促凝血作用，支持进一步研究s.c.康西珠单抗治疗血友病的潜在用途。
目的：为了评估单剂量康西单抗在健康志愿者和血友病A或B患者中的安全性并描述其药代动力学和药效学。
方法：在第一个人剂量中，第一阶段，多中心，随机化，双盲,安慰剂对照试验对健康志愿者(n=28)和血友病患者(n=24)给予单次静脉内(0.5-9000μgkg(-1))或皮下(50-3000μgkg(-1))剂量的康西珠单抗.
结果：康西单抗在单次静脉或皮下给药后具有良好的安全性。没有严重不良事件，也没有抗康单抗抗体。血小板无临床相关变化,凝血酶原时间,活化部分凝血活酶时间，纤维蛋白原，或者发现了抗凝血酶.康西单抗的剂量依赖性促凝血作用被视为D-二聚体和凝血酶原片段1+2的水平增加。由于靶标介导的清除，观察到了康西单抗的非线性药代动力学。在最高剂量下测量的最大平均AUC0-∞为33.960hμgmL(-1)和最大平均浓度为247μgmL(-1)。
结论：康西单抗在静脉或皮下给药后显示出良好的安全性，并且由于靶标介导的清除而观察到非线性药代动力学。观察到康西珠单抗的浓度依赖性促凝血作用，支持进一步研究s.c.康西珠单抗治疗血友病的潜在用途。
