Preclinical Pharmacology of Albumin-Free B-Domain Deleted Recombinant Factor VIII

Kenneth Brinkhous; Helena Sandberg; Lars Widlund; Marjorie Read; Timothy Nichols; Jeffery Sigman; Ulla Oswaldsson; Robert G. Schaub; Marianne Mikaelsson

doi:10.1055/s-2002-32661

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2002; 28(3): 269-272
DOI: 10.1055/s-2002-32661

Preclinical Pharmacology of Albumin-Free B-Domain Deleted Recombinant Factor VIII

Kenneth Brinkhous¹ , Helena Sandberg² , Lars Widlund² , Marjorie Read¹ , Timothy Nichols¹ , Jeffery Sigman¹ , Ulla Oswaldsson² , Robert G. Schaub³ , Marianne Mikaelsson²

¹University of North Carolina, Chapel Hill, Chapel Hill, North Carolina
²Pharmacia AB, Stockholm, Sweden
³Wyeth Research, Cambridge, Massachusetts

Abstract

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.

KEYWORDS

Hemophilia - recombinant factor VIII - B-domain deleted - canine - albumin free

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