Translational Pharmacokinetic/Pharmacodynamic Characterization and Target-Mediated Drug Disposition Modeling of an Anti–Tissue Factor Pathway Inhibitor Antibody, PF-06741086

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...

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Bibliographic Details
Published in:Journal of pharmaceutical sciences 2018-07, Vol.107 (7), p.1995-2004
Main Authors: Parng, Chuenlei, Singh, Pratap, Pittman, Debra D., Wright, Katherine, Leary, Beth, Patel-Hett, Sunita, Rakhe, Swapnil, Stejskal, James, Peraza, Marjorie, Dufield, Dawn, Murphy, John E., Webster, Rob
Format: Article
Language:English
Subjects:
human dose projection
mechanistic modeling
monoclonal antibody
non-linear pharmacokinetics
pharmacodynamics
TFPI
TMDD
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Summary: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.
ISSN:0022-3549
1520-6017
DOI:10.1016/j.xphs.2018.03.010