Institute of Thrombosis and Hemostasis and the National Hemophilia Center, The Chaim Sheba Medical Center, Tel Hashomer, affiliated to Sacker School of Medicine, Tel Aviv University, Israel.
Haemophilia. 2011 Nov;17(6):854-9. doi: 10.1111/j.1365-2516.2011.02495.x. Epub 2011 Mar 28.
Recombinant coagulation factor VIII (rFVIII) concentrates provide a safe and efficacious replacement therapy for treatment and prevention of bleeding in patients with severe haemophilia A. The aim of this study was to compare the pharmacokinetic (PK) and safety profiles of two serum-free rFVIII products: N8, a new rFVIII manufactured by Novo Nordisk and Advate(®), a marketed product. Patients with severe haemophilia A with >150 exposure days to FVIII, without current or past inhibitors, were enrolled in an open-label, first human dose (FHD), multicentre trial. Twenty-three patients first received a single dose of 50 IU kg(-1) body weight Advate(®) followed by 50 IU kg(-1) body weight N8 at the next visit. A 4-day washout period was required prior to each dosing. Blood samples for PK and safety analyses were drawn prior to dosing and at intervals up until 48 h postdosing. The PK parameters were based on FVIII clotting activity (FVIII:C) measurements. Occurrence of adverse events was closely monitored. The mean profiles of FVIII:C and all primary and secondary parameters for Advate(®) and N8 were comparable. The 90% CI for the treatment ratio (Advate(®)/N8) for all primary endpoints (incremental recovery, t(1/2), AUC and Cl), and the secondary endpoints (AUC(last) and C(max)) were within the bioequivalence interval of 0.8-1.25. There were no safety concerns in the study and no reports of inhibitor formation in the 72-h period following exposure to a single N8 dose. In conclusion, N8 is bioequivalent to Advate(®). Furthermore, N8 is well tolerated in the FHD trial.
新型重组凝血因子 VIII（rFVIII）浓缩物为严重甲型血友病患者的出血治疗和预防提供了安全有效的替代疗法。本研究旨在比较两种无血清 rFVIII 产品的药代动力学（PK）和安全性特征：N8，由 Novo Nordisk 生产的新型 rFVIII 和 Advate（®），一种市售产品。纳入了无当前或既往抑制剂、FVIII 暴露天数>150 天的严重甲型血友病患者，进行一项开放性、首次人体剂量（FHD）、多中心试验。23 例患者首次接受 50IU/kg 体重 Advate（®）单次剂量，下一次就诊时给予 50IU/kg 体重 N8。每次给药前需进行 4 天洗脱期。在给药前和给药后直至 48 小时内采集血样进行 PK 和安全性分析。PK 参数基于 FVIII 凝血活性（FVIII:C）测量。密切监测不良事件的发生情况。Advate（®）和 N8 的 FVIII:C 和所有主要和次要参数的平均曲线相似。所有主要终点（增量恢复、t(1/2)、AUC 和 Cl）和次要终点（AUC(last)和 C(max)）的治疗比值（Advate（®）/N8）的 90%置信区间均在 0.8-1.25 的生物等效性区间内。该研究未出现安全性问题，且在单次 N8 剂量暴露后 72 小时内未报告抑制剂形成。总之，N8 与 Advate（®）生物等效。此外，N8 在 FHD 试验中具有良好的耐受性。
