重组血管性血友病因子与血浆源性血管性血友病3型患者药动学-药效学比较

IF 2.1 Q3 HEMATOLOGY
Alexander Bauer, Sofia Friberg-Hietala, Giovanni Smania, Martin Wolfsegger
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引用次数: 0

摘要

背景:重组血管性血友病因子(rVWF, vonicog alfa, Vonvendi/Veyvondi, Takeda Pharmaceuticals USA, Lexington, MA)和几种血浆来源的VWF/因子VIII (pdVWF/FVIII)浓缩物可用于治疗血管性血友病(VWD)患者的出血发作。目的:建立人群药代动力学(PK)/药效学(PD)模型,描述静脉注射rVWF或pdVWF/FVIII浓缩物(VWF:RCo/FVIII: c2.4:1)后VWF:里斯托素辅助因子(VWF:RCo)活性随时间的变化及其与FVIII活性(FVIII:C)的关系;使用最终的PK/PD模型对rVWF和pdVWF/FVIII进行计算机比较。方法:rVWF的群体PK模型基于4项临床研究的数据,在这些研究中,rVWF被给予1、2或3型成年VWD患者(一期:NCT00816660;3期:NCT01410227和NCT02283268)或严重血友病A(1期:EudraCT 2011-004314-42)。pdVWF/FVIII的PK和PK/PD模型基于3型VWD患者接受rVWF +重组FVIII (rFVIII, octocog alfa, ADVATE®,Takeda Pharmaceuticals USA, Lexington, MA, USA)或pdVWF/FVIII的1期研究(NCT00816660)的数据。结果:与pdVWF/FVIII相比,rVWF在3型VWD中的清除率有显著差异,导致rVWF比pdVWF/FVIII的平均停留时间(即VWF:RCo活性在体内的持续时间)和半衰期延长约1.75。模拟结果表明,在重复给药rVWF (50 IU/kg)后,FVIII:C活性可以在整个72小时的给药间隔内保持>40 IU/dL。结论:与pdVWF/FVIII给药相比,rVWF给药后VWF:RCo的消除速度较慢,对FVIII转换的影响延长。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3.

Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3.

Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3.

Pharmacokinetic-Pharmacodynamic Comparison of Recombinant and Plasma-Derived von Willebrand Factor in Patients with von Willebrand Disease Type 3.

Background: Recombinant von Willebrand factor (rVWF, vonicog alfa, Vonvendi/Veyvondi, Takeda Pharmaceuticals USA, Lexington, MA) and several plasma-derived VWF/factor VIII (pdVWF/FVIII) concentrates are available for treating bleeding episodes in patients with von Willebrand disease (VWD).

Purpose: To develop population pharmacokinetic (PK)/pharmacodynamic (PD) models that describe VWF:ristocetin cofactor (VWF:RCo) activity and its relationship with FVIII activity (FVIII:C) over time following intravenous administration of either rVWF or a pdVWF/FVIII concentrate (VWF:RCo/FVIII:C 2.4:1) in patients with VWD; to use the final PK/PD models for an in silico comparison of rVWF and pdVWF/FVIII.

Methods: The population PK model for rVWF was based on data from four clinical studies in which rVWF was administered to adult patients with VWD type 1, 2 or 3 (phase 1: NCT00816660; phase 3: NCT01410227 and NCT02283268) or severe hemophilia A (phase 1: EudraCT 2011-004314-42). The PK and PK/PD models for pdVWF/FVIII were based on data from the phase 1 study (NCT00816660) in patients with type 3 VWD who received either rVWF plus recombinant FVIII (rFVIII, octocog alfa, ADVATE®, Takeda Pharmaceuticals USA, Lexington, MA, USA) or pdVWF/FVIII.

Results: There was a marked difference in clearance following rVWF administration compared with pdVWF/FVIII in type 3 VWD, leading to a ~1.75 longer mean residence time (ie, persistence of VWF:RCo activity in the body) and half-life for rVWF versus pdVWF/FVIII. Simulations showed that following repeated administration of rVWF (50 IU/kg), a FVIII:C activity of >40 IU/dL can be maintained for the full 72 h dosing interval.

Conclusion: The slower elimination of VWF:RCo following rVWF administration results in a prolonged effect on FVIII turnover compared with pdVWF/FVIII administration.

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来源期刊
CiteScore
3.50
自引率
0.00%
发文量
94
审稿时长
16 weeks
期刊介绍: The Journal of Blood Medicine is an international, peer-reviewed, open access, online journal publishing laboratory, experimental and clinical aspects of all topics pertaining to blood based medicine including but not limited to: Transfusion Medicine (blood components, stem cell transplantation, apheresis, gene based therapeutics), Blood collection, Donor issues, Transmittable diseases, and Blood banking logistics, Immunohematology, Artificial and alternative blood based therapeutics, Hematology including disorders/pathology related to leukocytes/immunology, red cells, platelets and hemostasis, Biotechnology/nanotechnology of blood related medicine, Legal aspects of blood medicine, Historical perspectives. Original research, short reports, reviews, case reports and commentaries are invited.
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