Research and Development, Novo Nordisk A/S, Novo Nordisk Park, 2760 Maaloev, Denmark.
Eur J Pharm Sci. 2011 Apr 18;42(5):578-83. doi: 10.1016/j.ejps.2011.02.013. Epub 2011 Mar 5.
NN1731 is a recombinant activated factor VII (rFVIIa) analogue with enhanced activity. The objective of the present study was to evaluate the clearance mechanisms of rFVIIa and NN1731 after intravenous administration to Beagle dogs.
The study was performed in Beagle dogs administered with a single dose of 5.4 nmol/kg rFVIIa or NN1731 intravenously. Plasma samples collected up to 12-h post-administration were analysed using three different assays to determine FVIIa clot activity (FVIIa:C), total FVIIa antigen, and levels of FVIIa-antithrombin (AT) complexes. Pharmacokinetic parameters were determined by use of standard non-compartmental and non-linear mixed effects methods.
For both compounds, complex formation with AT accounted for the observed difference between the activity and the antigen curves and constituted 60-70% of the total clearance. The clearance of rFVIIa and NN1731 was estimated to be 73 and 214 mL/h/kg, respectively, accordingly, AT complex formation occurred around three times faster for NN1731. The difference in activity observed in the initial phase, resulting in distribution half-lives of 0.71 and 0.22 h for rFVIIa and NN1731, was mainly caused by the 3-fold difference in clearance. The terminal half-life of rFVIIa and NN1731 was estimated to be 2.1 and 2.5 h, respectively. The non-compartmental analysis resulted in almost identical parameters.
The present study demonstrates that the difference between the activity and the antigen profiles of rFVIIa and NN1731 in Beagle dogs is the result of complex formation with AT which constitutes a major pathway for the clearance of rFVIIa activity.
NN1731 是一种具有增强活性的重组激活因子 VII（rFVIIa）类似物。本研究的目的是评估 rFVIIa 和 NN1731 在静脉给予比格犬后的清除机制。
本研究在静脉给予比格犬 5.4 nmol/kg rFVIIa 或 NN1731 单剂量后进行。使用三种不同的测定法分析在给药后 12 小时内采集的血浆样本，以确定 FVIIa 凝血活性（FVIIa：C）、总 FVIIa 抗原和 FVIIa-抗凝血酶（AT）复合物水平。使用标准非隔室和非线性混合效应方法确定药代动力学参数。
对于这两种化合物，与 AT 的复合物形成解释了活性和抗原曲线之间的差异，并构成了总清除的 60-70%。rFVIIa 和 NN1731 的清除率分别估计为 73 和 214 mL/h/kg，因此，NN1731 的 AT 复合物形成速度快约 3 倍。活性观察到的初始阶段的差异导致 rFVIIa 和 NN1731 的分布半衰期分别为 0.71 和 0.22 h，主要是由于清除率的 3 倍差异所致。rFVIIa 和 NN1731 的终末半衰期估计分别为 2.1 和 2.5 h。非隔室分析得出的参数几乎相同。
本研究表明，rFVIIa 和 NN1731 在比格犬中的活性和抗原谱之间的差异是与 AT 形成复合物的结果，这构成了 rFVIIa 活性清除的主要途径。
