title: Preclinical pharmacology of albumin-free B-domain deleted recombinant factor VIII.
abstract: A second-generation recombinant factor VIII molecule was developed with an albumin-free formulation. In this modified form of factor VIII, the N- and C-terminal sections of the B-domain are retained and fused at serine 743 and glutamine 1638, resulting in a B-domain deleted factor VIII protein known as ReFacto (Genetics Institute, Andover, MA). Preclinical studies of ReFacto have focused on efficacy of the product for the hemophilia A patient population. The efficacy and pharmacokinetic profiles of ReFacto were similar to plasma-derived factor VIII in correcting the hemostatic defect of hemophilia A dogs. Both ReFacto and plasma-derived human factor VIII (Octonativ-M7, Pharmacia, Stockholm, Sweden) were found to associate with von Willebrand factor (vWF) after infusion into hemophilia A dogs as demonstrated by size exclusion chromatography. Infusion of either ReFacto or Octonativ-M7 quickly corrected factor VIII coagulant activity (FVIIIc), whole blood clotting time (WBCT), and activated partial thromboplastin time (aPTT). No obvious differences were seen between ReFacto and Octonativ-M7. Both ReFacto and Octonativ-M7 treatment reduced secondary bleeding time to less than 6 minutes. The clearance was faster and the volume of distribution at steady state was larger for plasma-derived factor VIII compared with ReFacto. The half-life was similar between Octonativ-M7 and ReFacto. These data predict that ReFacto will be effective in correcting human factor VIII deficiency states.
authors.affiliation: University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Brinkhous
authors.forename: Helena
authors.initials: H
authors.lastname: Sandberg
authors.forename: Lars
authors.initials: L
authors.lastname: Widlund
authors.forename: Marjorie
authors.initials: M
authors.lastname: Read
authors.forename: Timothy
authors.initials: T
authors.lastname: Nichols
authors.forename: Jeffery
authors.initials: J
authors.lastname: Sigman
authors.forename: Ulla
authors.initials: U
authors.lastname: Oswaldsson
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schaub
authors.forename: Marianne
authors.initials: M
authors.lastname: Mikaelsson
mesh_terms: D000818:Animals; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005169:Factor VIII / Q000235:genetics* / Q000493:pharmacokinetics* / Q000494:pharmacology; D006467:Hemophilia A / Q000188:drug therapy; D015202:Protein Engineering; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000235:genetics* / Q000493:pharmacokinetics* / Q000494:pharmacology; D017384:Sequence Deletion
chemical_list: D011994:Recombinant Proteins; C078147:F8 protein, human; D005169:Factor VIII