Department of Small Animal Clinical Sciences, Faculty of Life Sciences, University of Copenhagen, Copenhagen, Denmark.
Haemophilia. 2011 Nov;17(6):962-70. doi: 10.1111/j.1365-2516.2011.02536.x. Epub 2011 Jun 6.
Recombinant human FVIIa (rhFVIIa) corrects the coagulopathy in hemophilia A and B as well as FVII deficiency. This is also the case in dogs until canine anti-human FVIIa antibodies develop (~2 weeks). Recombinant canine factor VIIa (rcFVIIa), successfully over-expressed by gene transfer in haemophilia dogs, has provided long-term haemostasis (>2 years). However, pharmacokinetics (PK), pharmacodynamics (PD) and safety of rcFVIIa after pharmacological administration have not been reported. We therefore wanted to explore the safety, PK and PD of rcFVIIa in dogs. A pilot study was set up to evaluate the safety as well as PK and PD of rcFVIIa after a single intravenous dose of 270 μg kg(-1) to one HA and one haemostatically normal dog and to directly compare rcFVIIa with rhFVIIa in these two dogs. Single doses of rcFVIIa and rhFVIIa were well tolerated. No adverse events were observed. Pharmacokinetic characteristics including half-life (FVIIa activity: 1.2-1.8 h; FVIIa antigen 2.8-3.7 h) and clearance were comparable for rcFVIIa and rhFVIIa. Kaolin-activated thromboelastography approached normal in the HA dog with the improvement being most pronounced after rcFVIIa. This study provided the first evidence that administering rcFVIIa intravenously is feasible, safe, well tolerated and efficacious in correcting the haemophilic coagulopathy in canine HA and that rcFVIIa exhibits pharmacokinetic characteristics comparable to rhFVIIa in haemophilic and haemostatically competent dogs. This strengthens the hypothesis that rcFVIIa can be administered to dogs to mimic the administration of rhFVIIa to humans.
重组人凝血因子 VIIa（rhFVIIa）可纠正血友病 A 和 B 以及 FVII 缺乏症患者的凝血功能障碍。在犬类中也是如此，直到犬类产生抗人 FVIIa 抗体（约 2 周）。通过基因转移在血友病犬中成功过表达的重组犬凝血因子 VIIa（rcFVIIa）已提供了长期止血（>2 年）。然而，尚未报道 rcFVIIa 在药理学给药后的药代动力学（PK）、药效学（PD）和安全性。因此，我们希望探索 rcFVIIa 在犬类中的安全性、PK 和 PD。我们开展了一项初步研究，以评估单次静脉注射 270μg/kg 的 rcFVIIa 在一只 HA 犬和一只止血正常的犬中的安全性、PK 和 PD，并直接比较这两只犬中 rcFVIIa 与 rhFVIIa 的情况。单剂量的 rcFVIIa 和 rhFVIIa 均耐受良好。未观察到不良反应。PK 特征包括半衰期（FVIIa 活性：1.2-1.8 小时；FVIIa 抗原：2.8-3.7 小时）和清除率在 rcFVIIa 和 rhFVIIa 之间具有可比性。在 HA 犬中，高岭土激活的血栓弹性描记法接近正常，rcFVIIa 的改善最为明显。这项研究首次提供了证据，证明静脉内给予 rcFVIIa 是可行、安全、耐受良好且有效的，可纠正犬类 HA 的血友病性凝血障碍，并且 rcFVIIa 在血友病和止血功能正常的犬中表现出与 rhFVIIa 相似的 PK 特征。这加强了 rcFVIIa 可用于模拟 rhFVIIa 对人类给药的假设。
