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

Autor:	Parng C; Pfizer Biomedicine Design, Cambridge, Massachusetts 02139. Electronic address: chuenlei.parng@pfizer.com., Singh P; Pfizer Biomedicine Design, Cambridge, Massachusetts 02139., Pittman DD; Pfizer Rare Disease Research Unit, Hematology, Cambridge, Massachusetts 02139., Wright K; Pfizer Biomedicine Design, Cambridge, Massachusetts 02139., Leary B; Pfizer Biomedicine Design, Cambridge, Massachusetts 02139., Patel-Hett S; Pfizer Rare Disease Research Unit, Hematology, Cambridge, Massachusetts 02139., Rakhe S; Pfizer Rare Disease Research Unit, Hematology, Cambridge, Massachusetts 02139., Stejskal J; Pfizer Drug Safety Research and Development, Cambridge, Massachusetts 02139., Peraza M; Pfizer Drug Safety Research and Development, Cambridge, Massachusetts 02139., Dufield D; Pfizer Biomedicine Design, Cambridge, Massachusetts 02139., Murphy JE; Pfizer Rare Disease Research Unit, Hematology, Cambridge, Massachusetts 02139., Webster R; Pfizer Biomedicine Design, Cambridge, Massachusetts 02139.
Jazyk:	angličtina
Zdroj:	Journal of pharmaceutical sciences [J Pharm Sci] 2018 Jul; Vol. 107 (7), pp. 1995-2004. Date of Electronic Publication: 2018 Mar 20.
DOI:	10.1016/j.xphs.2018.03.010
Abstrakt:	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. (Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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