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Pharmacological characteristics of a novel, recombinant fusion protein linking coagulation factor VII a with albumin (rVIIa‐FP)
Author(s) -
Zollner S.,
Schuermann D.,
Raquet E.,
MuellerCohrs J.,
Weimer T.,
Pragst I.,
Dickneite G.,
Schulte S.
Publication year - 2014
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.12477
Subject(s) - recombinant factor viia , pharmacokinetics , medicine , coagulation , pharmacology , pharmacodynamics , recombinant dna , factor ix , dosing , hemostasis , factor vii , in vivo , anesthesia , chemistry , surgery , biochemistry , biology , gene , microbiology and biotechnology
Summary Background Recombinant factor VII a (r FVII a) is approved for use in controlling bleeding episodes in people with hemophilia who have developed inhibitors to replacement therapy. Due to its short half‐life ( t ½ ), frequent injections are required, limiting its use as a prophylactic treatment. A novel, recombinant fusion protein linking coagulation factor VII a with albumin (r VII a‐ FP ) has been developed to extend the t ½ of r FVII a. Objectives The aim of our studies was to investigate the pharmacokinetic/pharmacodynamic characteristics of r VII a‐ FP in preclinical animal species. Methods Pharmacokinetic ( PK ) parameters were derived after single intravenous dosing in hemophilia A mice, rats, rabbits and monkeys. PK analysis was based on human FVII plasma levels determined by measuring FVII antigen levels by ELISA in mice and rats, and FVII a activity using STACLOT ® VII a‐r TF in rabbits and monkeys. Induction of thrombin generation was investigated in mice, while hemostatic activity was assessed by thrombus formation in rabbits. Results Compared with r FVII a, r VII a‐ FP displayed a prolonged t ½ , enhanced in vivo recovery and reduced clearance in all species investigated. In mice, 16 h after treatment with r VII a‐ FP , thrombin levels were quantifiable, indicating prolonged efficacy, whereas values had approached baseline at this time after treatment with r FVII a. After 12 h, hemostatic efficacy was negligible in r FVII a‐treated rabbits, but sustained in animals receiving r VII a‐ FP . Conclusions These studies indicate that the longer t ½ of r VII a‐ FP compared with r FVII a translates into extended activity. These findings suggest that r VII a‐ FP has the potential to be administered less frequently than r FVII a‐containing concentrates in clinical use.