The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination.
The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination.
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DOI：
10.1177/1076029618755947
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发表时间：
2018-07
期刊：
影响因子：
--
通讯作者：
Van Ryn J
中科院分区：
文献类型：
--
作者：
Glund S;Gan G;Moschetti V;Reilly P;Honickel M;Grottke O;Van Ryn J
Idarucizumab是一种人源化单克隆抗体片段（Fab），可快速持续逆转达比加群介导的抗凝作用。依达鲁珠单抗和达比加群主要通过肾脏消除。本分析旨在表征依达鲁珠单抗的肾消除，并研究依达鲁珠单抗对达比加群药代动力学（PK）的影响，反之则相反。研究在5/6只切除肾的大鼠、有或无肾损害的人类志愿者以及猪肝损伤模型中进行。在大鼠和人类中，肾脏损害增加了依达鲁珠单抗暴露和初始半衰期，但不影响其终末半衰期。未改变的依达鲁珠单抗尿排泄随着依达鲁珠单抗剂量的增加而增加，提示高剂量时肾小管再摄取过程饱和。达比加群不影响依达鲁珠单抗的PK。相比之下，idarucizumab给药导致达比加群重新分布到血浆中，在那里它被idarucizumab结合并灭活。服用依达鲁珠单抗后尿中达比加群的排泄延迟，但尿中排泄的达比加群总量未受影响。依达鲁珠单抗和达比加群通过肾脏途径一起消除。
Idarucizumab, a humanized monoclonal antibody fragment (Fab), provides rapid and sustained reversal of dabigatran-mediated anticoagulation. Idarucizumab and dabigatran are mainly eliminated via the kidneys. This analysis aimed to characterize the renal elimination of idarucizumab and investigate the influence of idarucizumab on the pharmacokinetics (PK) of dabigatran and vice versa. Studies were conducted in 5/6 nephrectomized rats, in human volunteers with and without renal impairment, and in a porcine liver trauma model. In both rats and humans, renal impairment increased idarucizumab exposure and initial half-life but did not affect its terminal half-life. Urinary excretion of unchanged idarucizumab increased with increasing idarucizumab dose, suggesting saturation of renal tubular reuptake processes at higher doses. The PK of idarucizumab was unaffected by dabigatran. In contrast, idarucizumab administration resulted in redistribution of dabigatran to the plasma, where it was bound and inactivated by idarucizumab. Urinary excretion of dabigatran after administration of idarucizumab was delayed, but total dabigatran excreted in urine was unaffected. Idarucizumab and dabigatran were eliminated together via renal pathways.
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影响因子：
13.6
作者：
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通讯作者：
Kozyraki, Renata
影响因子：
6.7
作者：
Glund, Stephan;Moschetti, Viktoria;Reilly, Paul
通讯作者：
Reilly, Paul
影响因子：
6.7
作者：
Honickel, Markus;Treutler, Stefanie;Grottke, Oliver
通讯作者：
Grottke, Oliver
影响因子：
2.9
作者：
Meibohm, Bernd;Zhou, Honghui
通讯作者：
Zhou, Honghui
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影响因子：
4.5
作者：
Glund S;Stangier J;van Ryn J;Schmohl M;Moschetti V;Haazen W;De Smet M;Gansser D;Norris S;Lang B;Reilly P;Kreuzer J
通讯作者：
Kreuzer J