Clearance of rFVIIa and NN1731 after intravenous administration to Beagle dogs
Clearance of rFVIIa and NN1731 after intravenous administration to Beagle dogs
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DOI：
10.1016/j.ejps.2011.02.013
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发表时间：
2011-04-18
影响因子：
4.6
通讯作者：
Ezban, Mirella
中科院分区：
文献类型：
--
作者：
Agerso, Henrik;Kristensen, Niels Rode;Ezban, Mirella
目的：NN 1731是一种活性增强的重组活化因子VII（rFVIIa）类似物。本研究的目的是评价Beagle dog.Methods静脉给药后rFVIIa和NN 1731的清除机制：本研究在Beagle dog.Methods中进行，单次静脉给药5.4 nmol/kg rFVIIa或NN 1731。使用三种不同的测定法分析给药后12小时内采集的血浆样品，以测定FVIIa凝块活性（FVIIa：C）、总FVIIa抗原和FVIIa-抗凝血酶（AT）复合物水平。通过使用标准的非房室模型和非线性混合效应methods.Results的药代动力学参数进行了测定：对于这两种化合物，与AT复合物的形成占观察到的活性和抗原曲线之间的差异，并构成总清除率的60-70%。估计rFVIIa和NN 1731的清除率分别为73和214 mL/h/kg，因此，NN 1731的AT复合物形成速度约为后者的3倍。在初始阶段观察到的活性差异（导致rFVIIa和NN 1731的分布半衰期为0.71和0.22 h）主要是由清除率的3倍差异引起的。rFVIIa和NN 1731的终末半衰期估计分别为2.1和2.5 h。非房室模型分析导致几乎相同的parameters.Conclusion：本研究表明，活性和rFVIIa和NN 1731在比格犬的抗原谱之间的差异是与AT形成复合物的结果，AT构成了清除rFVIIa活性的主要途径。(C)2011爱思唯尔有限公司版权所有。
Aim: 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.Methods: 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.Results: 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.Conclusion: 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. (C) 2011 Elsevier B.V. All rights reserved.