Pharmacokinetics and safety of a novel recombinant human von Willebrand factor manufactured with a plasma-free method: a prospective clinical trial.

Abstract

Safety and pharmacokinetics (PK) of recombinant von Willebrand factor (rVWF) combined at a fixed ratio with recombinant factor VIII (rFVIII) were investigated in 32 subjects with type 3 or severe type 1 von Willebrand disease (VWD) in a prospective phase 1, multicenter, randomized clinical trial. rVWF was well tolerated and no thrombotic events, inhibitors, or serious adverse events were observed. The PK of rVWF ristocetin cofactor activity, VWF antigen, and collagen-binding activity were similar to those of the comparator plasma-derived (pd) VWF-pdFVIII. In vivo cleavage of ultra-large molecular-weight rVWF multimers by ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13; the endogenous VWF protease) and generation of characteristic satellite bands were demonstrated. In 2 subjects with specific nonneutralizing anti-VWF-binding antibodies already detectable before rVWF infusion, a reduction in VWF multimers and VWF activity was observed. Stabilization of endogenous FVIII was enhanced following post-rVWF-rFVIII infusion as shown by the difference in area under the plasma concentration curve compared with pdVWF-pdFVIII (AUC0-∞) (P < .01). These data support the concept of administering rVWF alone once a therapeutic level of endogenous FVIII is achieved.

• Authors: Pier Mannuccio Mannucci, Christine Kempton, Carolyn Millar, Edward Romond, Amy Shapiro, Ingvild Birschmann, Margaret V Ragni, Joan Cox Gill, Thynn Thynn Yee, Robert Klamroth, Wing-Yen Wong, Miranda Chapman, Werner Engl, Peter L Turecek, Tobias M Suiter, Bruce M Ewenstein, rVWF Ad Hoc Study Group
• Journal: Blood (Blood) Vol. 122 Issue 5 Pg. 648-57 (Aug 01 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23777763 (Publication Type: Clinical Trial, Phase I, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Recombinant Proteins
• von Willebrand Factor

Topics

• Adolescent
• Adult
• Cross-Over Studies
• Double-Blind Method
• Female
• Humans
• Male
• Middle Aged
• Recombinant Proteins (adverse effects, pharmacokinetics, therapeutic use)
• Young Adult
• von Willebrand Diseases (drug therapy, metabolism)
• von Willebrand Factor (adverse effects, pharmacokinetics, therapeutic use)