组织因子途径抑制剂
药效学
药代动力学
药理学
体内
组织因子
凝血酶
凝结
单克隆抗体
药品
抗凝血酶
化学
抗体
血小板
基因亚型
医学
肝素
免疫学
内科学
生物
生物化学
生物技术
基因
作者
Chuenlei Parng,Pratap Singh,Debra D. Pittman,Katherine Wright,Beth Leary,Sunita Patel–Hett,Swapnil Rakhe,James Stejskal,Marjorie A. Peraza,Dawn Dufield,John E. Murphy,Rob Webster
标识
DOI:10.1016/j.xphs.2018.03.010
摘要
Tissue factor pathway inhibitor (TFPI) exhibits multiple isoforms, which are known to present in multiple locations such as plasma, endothelium, and platelets. TFPI is an endogenous negative modulator of the coagulation pathway, and therefore, neutralization of TFPI function can potentially increase coagulation activity. A human monoclonal antibody, PF-06741086, which interacts with all isoforms of TFPI is currently being tested in clinic for treating hemophilia patients with and without inhibitors. To support clinical development of PF-06741086, pharmacokinetics (PK) and pharmacodynamics of PF-06741086 were characterized in monkeys. In addition, a mechanistic model approach was used to estimate PK parameters in monkeys and simulate PK profiles in human. The results show that PF-06741086 exhibited target-mediated drug disposition and had specific effects on various hemostatic markers including diluted prothrombin time, thrombin generation, and thrombin-antithrombin complex in monkeys after administration. The model-predicted and observed human exposures were compared retrospectively, and the result indicates that the exposure prediction was reasonable within less than 2-fold deviation. This study demonstrated in vivo efficacy of PF-06741086 in monkeys and the utility of a rational mechanistic approach to describe PK for a monoclonal antibody with complex target binding.
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