Favaloro Emmanuel J, Lloyd John, Rowell John, Baker Ross, Rickard Kevin, Kershaw Geoff, Street Alison, Scarff Kate, Barrese Giulio, Maher Darryl, McLachlan Andrew J
Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, SWAHS, Westmead, NSW, 2145, Australia.
Thromb Haemost. 2007 Jun;97(6):922-30.
Plasma-derived factor concentrates are important in the management of von Willebrand disorder (VWD). In our geographic locality, a single viral inactivation step concentrate (AHF [High Purity]), has been replaced with one using a double viral inactivation step (Biostate). The aim of this study was to compare the pharmacokinetics of von Willebrand factor (VWF) and factor VIII (FVIII) after administration of AHF (High Purity) and Biostate. This study was a single-blind, randomised cross-over, multi-centre investigation in twelve people with VWD, comprising four type 3, two type 2B, one type 2M and five type 1 VWD. The subjects received a single infusion of 60 IU/kg ristocetin cofactor activity (VWF:RCo) of either AHF (High Purity) or Biostate, and after a minimum 15-day wash-out period they received the alternative product. Blood samples were collected for up to 48 hours after each dose for assay of FVIII coagulant activity (FVIII:C) and VWF by VWF:RCo, collagen binding capacity (VWF:CB) and antigen (VWF:Ag). As a measure of delivered VWF 'functionality' we calculated the area-under-the-concentration-time-curve (AUC) ratios of VWF:RCo to VWF:Ag and VWF:CB to VWF:Ag. The effect on platelet adhesiveness by PFA-100 closure times (CTs) was measured prior to and 30 minutes post infusion. VWF multimers were also assessed pre and post infusion. Pharmacokinetic parameters after AHF (High Purity) and Biostate were in close agreement for VWF:RCo (confirming dosing equivalence). Parameters for other study markers were also similar, although Biostate tended to yield relatively lower VWF:Ag and higher VWF:CB levels. Although AHF (High Purity) and Biostate resulted in similar levels of high-molecular-weight (HMW) multimers post-infusion, the relative level of HMW to low-molecular-weight (LMW) multimers were determined to be higher following Biostate. The relative levels of functional VWF (i.e. VWF:CB and VWF:RCo) to VWF:Ag were also higher in Biostate compared to AHF (High Purity). With both study products, PFA-100 CTs 30 minutes post infusion showed minor improvement for only some subjects. In conclusion, the pharmacokinetics of FVIII:C and VWF are not significantly different after administration of AHF (High Purity) and Biostate. Study parameters considered as 'in-vitro' markers of VWF 'functionality' or potential clinical efficacy (i.e. VWF:CB and VWF:RCo relative to VWF:Ag, level of HMW VWF relative to LMW-VWF) were determined to be higher for Biostate than AHF (High Purity). PFA-100 CTs did not adequately reflect changes in these VWF parameters. Based on these results, one would expect Biostate to be at least as effective, if not superior to AHF (High Purity) for the treatment of VWD.
血浆源性因子浓缩物在血管性血友病（VWD）的治疗中具有重要作用。在我们所在地区，单一病毒灭活步骤的浓缩物（AHF[高纯度]）已被采用双重病毒灭活步骤的浓缩物（Biostate）所取代。本研究的目的是比较给予AHF（高纯度）和Biostate后血管性血友病因子（VWF）和凝血因子VIII（FVIII）的药代动力学。本研究是一项针对12名VWD患者的单盲、随机交叉、多中心研究，其中包括4例3型、2例2B型、1例2M型和5例1型VWD患者。受试者接受一次60 IU/kg瑞斯托霉素辅因子活性（VWF:RCo）的AHF（高纯度）或Biostate输注，在至少15天的洗脱期后，他们接受另一种产品。每次给药后最多采集48小时的血样，用于检测FVIII凝血活性（FVIII:C）以及通过VWF:RCo、胶原结合能力（VWF:CB）和抗原（VWF:Ag）检测VWF。作为所递送VWF“功能”的一种衡量指标，我们计算了VWF:RCo与VWF:Ag以及VWF:CB与VWF:Ag的浓度-时间曲线下面积（AUC）比值。在输注前和输注后30分钟测量PFA-100封闭时间（CTs）对血小板黏附性的影响。还在输注前后评估VWF多聚体。AHF（高纯度）和Biostate给药后的VWF:RCo药代动力学参数密切一致（证实给药等效性）。其他研究标志物的参数也相似，尽管Biostate往往产生相对较低的VWF:Ag水平和较高的VWF:CB水平。尽管AHF（高纯度）和Biostate输注后产生的高分子量（HMW）多聚体水平相似，但Biostate后HMW与低分子量（LMW）多聚体的相对水平更高。与AHF（高纯度）相比，Biostate中功能性VWF（即VWF:CB和VWF:RCo）与VWF:Ag的相对水平也更高。使用两种研究产品时，输注后30分钟的PFA-100 CTs仅对部分受试者显示出轻微改善。总之，给予AHF（高纯度）和Biostate后，FVIII:C和VWF的药代动力学无显著差异。被视为VWF“功能”或潜在临床疗效的“体外”标志物的研究参数（即VWF:CB和VWF:RCo相对于VWF:Ag、HMW VWF相对于LMW-VWF的水平）经测定Biostate高于AHF（高纯度）。PFA-100 CTs未能充分反映这些VWF参数的变化。基于这些结果，人们预期Biostate在治疗VWD方面至少与AHF（高纯度）一样有效，甚至可能更优。
