Comparison of the pharmacokinetics of two von Willebrand factor concentrates [Biostate and AHF (High Purity)] in people with von Willebrand disorder

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.

Pharmacokinetics, efficacy, and safety of a plasma-derived VWF/FVIII concentrate (VONCENTO) for on-demand and prophylactic treatment in patients with von Willebrand disease (SWIFT-VWD study)

“…The pharmacokinetic analyses results of this study were very similar to those in another BIOSTATE/VONCENTO study conducted in study participants with severe VWD (Study CSLST-BIO-00–75). In this Australian study (study period 2003), the pharmacokinetic profile of BIOSTATE was evaluated in 12 study participants with VWD where DDAVP treatment was deemed to be ineffective, inadequate or contraindicated [ 20 ]. The mean half-life values ± SD of VWF : RCo, VWF : Ag and VWF : CB observed in study CSLST-BIO-00–75 [11.6 (6.9), 13.9 (3.8) and 12.2 (4.2) h, respectively] were slightly lower than in this current study [13.7 (9.2), 18.3 (4.0) and 16.0 (4.0) h, respectively].…”

Human plasma-derived FVIII/VWD concentrate (Biostate): a review of experimental and clinical pharmacokinetic, efficacy and safety data

“…Patients were randomly assigned a single intravenous infusion of either Biostate or AHF-HP (60 IU/kg VWF:RCo; Infusion 1), followed by a 15-day washout period before administration of the alternate study concentrate (Infusion 2). Quantitative parameters for FVIII:C, VWF:RCo, VWF:CB and VWF:Ag, in addition to HMWM analysis and investigation of primary haemostasis parameters (evaluated using the PFA-100 assay [Siemens Healthcare]), were assessed at screening, before and 30 minutes after Infusions 1 and 2, and at the completion visit [ 31 ].…”

“…The PK properties following a single administration of Biostate are shown in Table 3 [ 31 ]. Area under curve (AUC) values for Biostate demonstrated similar PK properties to AHF-HP and other FVIII/VWF concentrates [ 31 ].…”

“…The PK properties following a single administration of Biostate are shown in Table 3 [ 31 ]. Area under curve (AUC) values for Biostate demonstrated similar PK properties to AHF-HP and other FVIII/VWF concentrates [ 31 ]. A high ratio of HMWM to low-MWM VWF was reported following infusion with Biostate and mirrored the observed high AUC ratios for VWF:RCo/VWF:Ag (0.85) and VWF:CB/VWF:Ag (0.61).…”

Intravascular recovery of VWF and FVIII following intraperitoneal injection and differences from intravenous and subcutaneous injection in mice

“…11-13 Both VWF and FVIII are large adhesive proteins and intravenous infusion studies in humans suggest that both proteins remain intravascular in contrast to other coagulation proteins, such as factor IX (FIX). 14-16 When FIX is injected intraperitoneally (IP) or subcutaneously (SC) it does achieve access to the vasculature. 17 Large proteins, like VWF and FVIII, have been presumed to be inefficiently transferred into the vascular space after SC or IP administration.…”