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A first‐in‐human study of the safety, tolerability, pharmacokinetics and pharmacodynamics of PF‐06741086, an anti‐tissue factor pathway inhibitor mAb, in healthy volunteers
Author(s): ,
M. Cardinal
Affiliations:
Rare Disease Research Unit, Pfizer Inc., Cambridge, USA
Correspondence: Matthew Cardinal, Clinician Rare Disease Research Unit, Clinical R&D Pfizer, Worldwide Research & Development, 610 Main St, 3rd Floor, RDRU, Cambridge, MA 02139, USA|Tel.: +1 617 800 7405|E‐mail: Matthew.H.Cardinal@pfizer.com
,
C. Kantaridis
Affiliations:
Pfizer Clinical Research Unit, Brussels, Belgium
,
T. Zhu
Affiliations:
Early Clinical Development, Pfizer Inc., Cambridge, USA
,
P. Sun
Affiliations:
Early Clinical Development, Pfizer Inc., Cambridge, USA
,
D. D. Pittman
Affiliations:
Rare Disease Research Unit, Pfizer Inc., Cambridge, USA
,
J. E. Murphy
Affiliations:
Rare Disease Research Unit, Pfizer Inc., Cambridge, USA
S. Arkin
Affiliations:
Rare Disease Research Unit, Pfizer Inc., Cambridge, USA
ISTH Academy. Cardinal M. Sep 4, 2018; 230963
Matthew Cardinal
Matthew Cardinal

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Journal Abstract
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Background
Tissue factor pathway inhibitor (TFPI) is a protease inhibitor of the tissue factor–activated factor VII complex and activated FX. PF‐06741086 is a mAb that targets TFPI to increase clotting activity.
Objectives
This study was a randomized, double‐blind, sponsor‐open, placebo‐controlled, single intravenous or subcutaneous dose escalation study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of PF‐06741086.
Patients/Methods
Volunteers who provided written informed consent were assigned to cohorts with escalating dose levels. Safety endpoints included treatment‐emergent adverse events (TEAEs), infusion/injection site reactions, vital signs, electrocardiogram, and coagulation and hematology laboratory parameters. Pharmacokinetic (PK) and pharmacodynamic (PD) endpoints included exposures of PF‐06741086 in plasma and measures of PF‐06741086 pharmacology, respectively.
Results
Forty‐one male volunteers were recruited overall. Thirty‐two were dosed with PF‐06741086 from 30 mg subcutaneously to 440 mg intravenously. All doses were safe and well tolerated. TEAEs were mild or moderate in severity, laboratory abnormalities were transient, there were no serious adverse events, there were no infusion/injection site reactions, and no dose escalation stopping criteria were met. Plasma exposures of PF‐06741086 increased greater than proportionally with dose under the same dosing route. Coagulation pharmacology was demonstrated via total TFPI, dilute prothrombin time, D‐dimer, prothrombin fragment 1 + 2 and thrombin generation assay parameters.
Conclusions
Single doses of PF‐06741086 at multiple dose levels were safe and well tolerated in a healthy adult male population. The safety, PK and PD data from this study support progression to a multiple‐dose study in hemophilic patients.
Keyword(s)
antibodies, monoclonal, blood, pharmacokinetics, pharmacology, safety
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