Structure and Function of Recombinant versus Plasma-Derived von Willebrand Factor and Impact on Multimer Pharmacokinetics in von Willebrand Disease.

Abstract

Recombinant von Willebrand factor (rVWF, vonicog alfa) is a purified VWF concentrate produced from Chinese hamster ovary cells. rVWF is not exposed to the VWF-cleaving protease ADAMTS13 and so is not subject to proteolytic degradation of large (L) and ultra-large (UL) VWF multimers by that enzyme. To compare the structure and function of rVWF with the human plasma-derived VWF [pdVWF] concentrates Haemate P®/Humate-P®, Voncento®, Wilate®/Eqwilate®, and Wilfactin®/Willfact®; to investigate the relationship between VWF multimeric pattern and VWF:ristocetin cofactor (VWF:RCo) activity through population pharmacokinetic (PK) modeling in patients with severe von Willebrand disease (VWD) treated with rVWF. Analyses included VWF:RCo activity, VWF:collagen-binding activity, VWF:platelet glycoprotein Ib receptor binding, factor VIII (FVIII) binding capacity, and VWF-mediated platelet adhesion under flow conditions. VWF multimeric structure was determined by agarose gel electrophoresis. Population PK models describing the activity-time profile of small, medium, and L/UL multimers following intravenous administration of rVWF in patients with severe VWD were developed. Findings demonstrate that rVWF contains a non-degraded VWF multimer pattern including the UL multimers not present in pdVWF concentrates. rVWF displayed higher specific platelet-binding activity, and faster mediation of platelet adhesion to collagen under shear stress versus pdVWF concentrates. rVWF also demonstrated higher FVIII binding capacity than Haemate P®, Voncento® and Wilate®. Modeling provided evidence that VWF:RCo activity in patients with severe VWD treated with rVWF is associated with L/UL VWF multimers in the circulation. Findings suggest that the L and UL multimers preserved in rVWF contribute to high biological activity and might be important for providing hemostatic efficacy.