Valentino L A, Cong L, Enockson C, Song X, Scheiflinger F, Muchitsch E M, Turecek P L, Hakobyan N
Rush University, Deerfield, IL, USA.
Haemophilia. 2015 Jan;21(1):58-63. doi: 10.1111/hae.12532. Epub 2014 Dec 2.
Prophylaxis prevents joint and other bleeding episodes in patients with haemophilia A. Development of new factor concentrates with longer circulating half-lives may encourage patients to start, continue or resume prophylaxis. The aim of this study was to compare the pharmacodynamic effect of a PEGylated full-length recombinant factor VIII (rFVIII) concentrate with that of an unmodified rFVIII concentrate with respect to the duration of prophylactic efficacy in a murine model of haemophilic joint bleeding. Mice were pretreated with BAX 855 or unmodified rFVIII at specified times before right knee puncture to induce haemarthrosis; left knee joints served as controls. Joint bleeding was evaluated using a combination of visual and histological assessments. Administration of a single dose of unmodified rFVIII before joint puncture prevented haemarthrosis in mice up to 24 h, whereas pretreatment with BAX 855 protected the joint from bleeding up to 48 h. This pharmacodynamic study showed prolonged efficacy of BAX 855 compared to ADVATE in a haemophilia A mouse joint bleeding model. This finding supports the possibility of using BAX 855 to increase FVIII trough levels and/or extend the dosing interval in patients with haemophilia A on prophylaxis, which may potentially improve prophylactic efficacy and long-term adherence.
预防性治疗可预防甲型血友病患者的关节及其他出血事件。开发具有更长循环半衰期的新型凝血因子浓缩物可能会促使患者开始、继续或恢复预防性治疗。本研究的目的是在血友病性关节出血小鼠模型中，比较聚乙二醇化全长重组凝血因子VIII（rFVIII）浓缩物与未修饰的rFVIII浓缩物在预防性治疗效果持续时间方面的药效学作用。在右膝关节穿刺诱导关节积血前的特定时间，用BAX 855或未修饰的rFVIII对小鼠进行预处理；左膝关节作为对照。使用视觉和组织学评估相结合的方法评估关节出血情况。在关节穿刺前给予单剂量未修饰的rFVIII可预防小鼠关节积血长达24小时，而用BAX 855预处理可使关节免受出血影响长达48小时。这项药效学研究表明，在甲型血友病小鼠关节出血模型中，与ADVATE相比，BAX 855具有更长的疗效。这一发现支持了在接受预防性治疗的甲型血友病患者中使用BAX 855来提高FVIII谷浓度和/或延长给药间隔的可能性，这可能会潜在地提高预防性治疗效果和长期依从性。
