Biopharmaceutical Research Unit, Novo Nordisk A/S, Måløv, Denmark.
Haemophilia. 2011 Sep;17(5):e963-8. doi: 10.1111/j.1365-2516.2011.02580.x. Epub 2011 Jun 20.
N8, a new recombinant factor VIII (rFVIII) compound developed for the treatment of haemophilia A, is produced in Chinese hamster ovary (CHO) cells and formulated without human- or animal-derived materials. The aim of the present study was to compare the pharmacokinetics (PK) and the procoagulant effect, measured by ex vivo whole blood clot formation, of N8 and a commercial rFVIII in a cross-over study in haemophilia A dogs. N8 and Advate® (100 IU kg⁻¹) were administered intravenously to three haemophilia A dogs. Blood was sampled between 0 and 120 h postdose and FVIII:C analysed. PK parameters maximum plasma concentration, area under the curve, half-life (t(½)), clearance, mean residence time (MRT) and volume of distribution and incremental recovery were calculated. Whole blood clotting time (WBCT) and thromboelastography (TEG®) were used to determine the haemostatic potential. No adverse reactions were observed with N8 or Advate ®. N8 and Advate® exhibited similar PK parameters, with t(½) 7.7-11 h and MRT 11-14 h. Both rFVIII compounds corrected the prolonged WBCT (> 48 min) to the range of normal dogs (8-12 min), i.e. N8 to 7.5-10.5 min and Advate® to 7.5-11.5 min. N8 and Advate® also normalized the whole blood clot formation according to TEG®. The native whole blood clotting assays (WBCT, TEG®) appeared to be more sensitive to low concentrations of FVIII than assays in citrated plasma samples. In conclusion, comparison of N8 and Advate ® in haemophilia A dogs revealed similar safety, similar PK and similar effects in whole blood clot formation assays.
N8 是一种新型的重组凝血因子 VIII（rFVIII）复合物，用于治疗 A 型血友病，它是在仓鼠卵巢（CHO）细胞中产生的，并且不含人源或动物源材料。本研究旨在比较 N8 和一种商业 rFVIII 在 A 型血友病犬中的药代动力学（PK）和促凝作用（通过体外全血凝结形成来测量）。N8 和 Advate®（100 IU kg⁻¹）静脉内给药至 3 只 A 型血友病犬。在给药后 0 至 120 小时之间采集血液样本，并分析 FVIII:C。计算 PK 参数：最大血浆浓度、曲线下面积、半衰期（t(½)）、清除率、平均驻留时间（MRT）和分布容积以及增量恢复。全血凝固时间（WBCT）和血栓弹性描记术（TEG®）用于确定止血潜能。N8 或 Advate ®均未观察到不良反应。N8 和 Advate®表现出相似的 PK 参数，t(½)为 7.7-11 小时，MRT 为 11-14 小时。两种 rFVIII 化合物均将延长的 WBCT（>48 分钟）纠正至正常犬的范围（8-12 分钟），即 N8 为 7.5-10.5 分钟，Advate®为 7.5-11.5 分钟。N8 和 Advate®还根据 TEG®使全血凝结形成正常化。与在枸橼酸盐血浆样本中的测定相比，天然全血凝固测定（WBCT、TEG®）似乎对低浓度的 FVIII 更敏感。总之，N8 和 Advate ®在 A 型血友病犬中的比较显示出相似的安全性、相似的 PK 和相似的全血凝结形成测定中的作用。
