Biopharmaceuticals Research Unit, Novo Nordisk A/S, Måløv, Denmark.
Br J Haematol. 2011 Jan;152(1):99-107. doi: 10.1111/j.1365-2141.2010.08432.x. Epub 2010 Nov 18.
NN1731 is a recombinant activated factor VII (rFVIIa) analogue with increased intrinsic activity. This also applies to its reactivity towards antithrombin (AT), the role of which was investigated in a pharmacokinetic (PK) study. NN1731 or rFVIIa was administered to normal and haemophilia A dogs and elimination was measured by FVIIa clot activity, FVIIa- and FVIIa-AT antigen. In vitro AT complex formation was studied in canine plasma spiked with NN1731 or rFVIIa. Based on FVIIa antigen concentrations, PK profiles in normal and haemophilia A dogs were similar for NN1731 and rFVIIa with antigen half lives, t(½) ≈1·8 h. In contrast, PK profiles based on activity measurements were distinctly different. NN1731 induced a strong, short lasting (t(½) ≈0·5 h) pro-coagulant response, whereas rFVIIa induced a lower, longer lasting (t(½) ≈1·1 h) response. Western Blot and FVIIa-AT antigen analysis demonstrated in vivo AT complex formation that accounted for these divergences. AT complex formation with FVIIa or NN1731 in vitro in canine plasma was considerably slower than the in vivo reaction. The results suggest that in vivo inhibition by AT contributes significantly to define drug duration in haemophilia treatment with rFVIIa and in particular with the NN1731 analogue.
NN1731 是一种重组激活的因子 VII（rFVIIa）类似物，具有增强的内在活性。这也适用于它对抗凝血酶（AT）的反应性，其作用在一项药代动力学（PK）研究中进行了研究。NN1731 或 rFVIIa 被给予正常和血友病 A 犬，并通过 FVIIa 凝块活性、FVIIa 和 FVIIa-AT 抗原来测量消除。在犬血浆中加入 NN1731 或 rFVIIa 研究了体外 AT 复合物形成。基于 FVIIa 抗原浓度，正常和血友病 A 犬的 PK 图谱对于 NN1731 和 rFVIIa 相似，抗原半衰期 t(½)≈1.8 h。相比之下，基于活性测量的 PK 图谱明显不同。NN1731 诱导强烈的、短暂的（t(½)≈0.5 h）促凝反应，而 rFVIIa 诱导较低的、持续时间较长的（t(½)≈1.1 h）反应。Western Blot 和 FVIIa-AT 抗原分析证明了体内 AT 复合物形成，这解释了这些差异。体外犬血浆中 FVIIa 或 NN1731 与 AT 的复合物形成明显慢于体内反应。结果表明，体内 AT 的抑制作用对 rFVIIa 治疗血友病以及特别是 NN1731 类似物的药物持续时间有重要影响。
