title: Comparison of the pharmacokinetics of two von Willebrand factor concentrates [Biostate and AHF (High Purity)] in people with von Willebrand disorder. A randomised cross-over, multi-centre study.
abstract: Plasma-derived factor concentrates are important in the management of von Willebrand disorder (VWD). In our geographic locality, a single viral inactivation step concentrate (AHF [High Purity]), has been replaced with one using a double viral inactivation step (Biostate). The aim of this study was to compare the pharmacokinetics of von Willebrand factor (VWF) and factor VIII (FVIII) after administration of AHF (High Purity) and Biostate. This study was a single-blind, randomised cross-over, multi-centre investigation in twelve people with VWD, comprising four type 3, two type 2B, one type 2M and five type 1 VWD. The subjects received a single infusion of 60 IU/kg ristocetin cofactor activity (VWF:RCo) of either AHF (High Purity) or Biostate, and after a minimum 15-day wash-out period they received the alternative product. Blood samples were collected for up to 48 hours after each dose for assay of FVIII coagulant activity (FVIII:C) and VWF by VWF:RCo, collagen binding capacity (VWF:CB) and antigen (VWF:Ag). As a measure of delivered VWF 'functionality' we calculated the area-under-the-concentration-time-curve (AUC) ratios of VWF:RCo to VWF:Ag and VWF:CB to VWF:Ag. The effect on platelet adhesiveness by PFA-100 closure times (CTs) was measured prior to and 30 minutes post infusion. VWF multimers were also assessed pre and post infusion. Pharmacokinetic parameters after AHF (High Purity) and Biostate were in close agreement for VWF:RCo (confirming dosing equivalence). Parameters for other study markers were also similar, although Biostate tended to yield relatively lower VWF:Ag and higher VWF:CB levels. Although AHF (High Purity) and Biostate resulted in similar levels of high-molecular-weight (HMW) multimers post-infusion, the relative level of HMW to low-molecular-weight (LMW) multimers were determined to be higher following Biostate. The relative levels of functional VWF (i.e. VWF:CB and VWF:RCo) to VWF:Ag were also higher in Biostate compared to AHF (High Purity). With both study products, PFA-100 CTs 30 minutes post infusion showed minor improvement for only some subjects. In conclusion, the pharmacokinetics of FVIII:C and VWF are not significantly different after administration of AHF (High Purity) and Biostate. Study parameters considered as 'in-vitro' markers of VWF 'functionality' or potential clinical efficacy (i.e. VWF:CB and VWF:RCo relative to VWF:Ag, level of HMW VWF relative to LMW-VWF) were determined to be higher for Biostate than AHF (High Purity). PFA-100 CTs did not adequately reflect changes in these VWF parameters. Based on these results, one would expect Biostate to be at least as effective, if not superior to AHF (High Purity) for the treatment of VWD.
authors.affiliation: Haematology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, SWAHS, Westmead, NSW, 2145, Australia. emmanuel@icpmr.wsahs.nsw.gov.au
authors.forename: Emmanuel J
authors.initials: EJ
authors.lastname: Favaloro
authors.forename: John
authors.initials: J
authors.lastname: Lloyd
authors.forename: John
authors.initials: J
authors.lastname: Rowell
authors.forename: Ross
authors.initials: R
authors.lastname: Baker
authors.forename: Kevin
authors.initials: K
authors.lastname: Rickard
authors.forename: Geoff
authors.initials: G
authors.lastname: Kershaw
authors.forename: Alison
authors.initials: A
authors.lastname: Street
authors.forename: Kate
authors.initials: K
authors.lastname: Scarff
authors.forename: Giulio
authors.initials: G
authors.lastname: Barrese
authors.forename: Darryl
authors.initials: D
authors.lastname: Maher
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: McLachlan
mesh_terms: D019540:Area Under Curve; D001315:Australia; D001780:Blood Coagulation Tests; D003029:Coagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004338:Drug Combinations; D005169:Factor VIII / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D006801:Humans; D007262:Infusions, Intravenous; D010973:Platelet Adhesiveness / Q000187:drug effects; D016037:Single-Blind Method; D013810:Therapeutic Equivalency; D016896:Treatment Outcome; D014842:von Willebrand Diseases / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D014841:von Willebrand Factor / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*
chemical_list: D003029:Coagulants; D004338:Drug Combinations; D014841:von Willebrand Factor; D005169:Factor VIII