title: Pharmacological characteristics of a novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP).
abstract: BACKGROUND
  Recombinant factor VIIa (rFVIIa) 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 (t½), frequent injections are required, limiting its use as a prophylactic treatment. A novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP) has been developed to extend the t(½) of rFVIIa.
  
  
  OBJECTIVE
  The aim of our studies was to investigate the pharmacokinetic/pharmacodynamic characteristics of rVIIa-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 FVIIa activity using STACLOT® VIIa-rTF 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 rFVIIa, rVIIa-FP displayed a prolonged t(½), enhanced in vivo recovery and reduced clearance in all species investigated. In mice, 16 h after treatment with rVIIa-FP, thrombin levels were quantifiable, indicating prolonged efficacy, whereas values had approached baseline at this time after treatment with rFVIIa. After 12 h, hemostatic efficacy was negligible in rFVIIa-treated rabbits, but sustained in animals receiving rVIIa-FP.
  
  
  CONCLUSIONS
  These studies indicate that the longer t(½) of rVIIa-FP compared with rFVIIa translates into extended activity. These findings suggest that rVIIa-FP has the potential to be administered less frequently than rFVIIa-containing concentrates in clinical use.
authors.affiliation: CSL Behring AG, Bern, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Zollner
authors.forename: D
authors.initials: D
authors.lastname: Schuermann
authors.forename: E
authors.initials: E
authors.lastname: Raquet
authors.forename: J
authors.initials: J
authors.lastname: Mueller-Cohrs
authors.forename: T
authors.initials: T
authors.lastname: Weimer
authors.forename: I
authors.initials: I
authors.lastname: Pragst
authors.forename: G
authors.initials: G
authors.lastname: Dickneite
authors.forename: S
authors.initials: S
authors.lastname: Schulte
mesh_terms: D000418:Albumins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D015942:Factor VIIa / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D006467:Hemophilia A / Q000188:drug therapy; D008252:Macaca fascicularis; D051379:Mice; D011517:Prothrombin Time; D011817:Rabbits; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000418:Albumins; D011993:Recombinant Fusion Proteins; D015942:Factor VIIa
keywords: half‐life; hemophilia; hemostasis; inhibitors; pharmacokinetics