title: 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.affiliation: Hemophilia and Thrombosis Center and Scientific Direction, IRCCS Ca' Granda Maggiore Policlinico Hospital Foundation and University of Milan, Milan, Italy;
authors.forename: Pier Mannuccio
authors.initials: PM
authors.lastname: Mannucci
authors.forename: Christine
authors.initials: C
authors.lastname: Kempton
authors.forename: Carolyn
authors.initials: C
authors.lastname: Millar
authors.forename: Edward
authors.initials: E
authors.lastname: Romond
authors.forename: Amy
authors.initials: A
authors.lastname: Shapiro
authors.forename: Ingvild
authors.initials: I
authors.lastname: Birschmann
authors.forename: Margaret V
authors.initials: MV
authors.lastname: Ragni
authors.forename: Joan Cox
authors.initials: JC
authors.lastname: Gill
authors.forename: Thynn Thynn
authors.initials: TT
authors.lastname: Yee
authors.forename: Robert
authors.initials: R
authors.lastname: Klamroth
authors.forename: Wing-Yen
authors.initials: WY
authors.lastname: Wong
authors.forename: Miranda
authors.initials: M
authors.lastname: Chapman
authors.forename: Werner
authors.initials: W
authors.lastname: Engl
authors.forename: Peter L
authors.initials: PL
authors.lastname: Turecek
authors.forename: Tobias M
authors.initials: TM
authors.lastname: Suiter
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Ewenstein
mesh_terms: D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D055815:Young Adult; D014842:von Willebrand Diseases / Q000188:drug therapy* / Q000378:metabolism*; D014841:von Willebrand Factor / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D011994:Recombinant Proteins; D014841:von Willebrand Factor