Abstract Number: PB1544
Meeting: ISTH 2020 Congress
Background: Recombinant von Willebrand factor (rVWF, vonicog alfa; Baxalta US Inc., a Takeda company, Lexington, MA, USA) is a VWF replacement therapy for von Willebrand disease (VWD). Unlike plasma-derived (pd)VWF, rVWF is not exposed to enzymatic proteolysis and has an intact multimer pattern that contains higher proportions of large and ultra-large (L/UL) multimers than pdVWF. Modelling pharmacokinetic (PK) profiles of small (S), medium (M), and L/UL multimers following rVWF dosing could help understand how the contributions of these multimers affect VWF:ristocetin cofactor (RCo) activity, a functional measure of VWF platelet binding activity.
Aims: To develop population PK models describing activity-time profiles of S, M, and L/UL multimers following intravenous rVWF dosing and compare multimer kinetics with those of VWF:RCo.
Methods: Population PK models were developed using non-linear mixed-effects modeling based on multimer distribution data from a phase 3 study in patients with severe VWD receiving 50 or 80 IU/kg VWF:RCo rVWF (n=36) (NCT01410227; ethics committee approval and patients’ informed consent were obtained). Multimer PK profiles were derived through scaling the proportion of S, M, and L/UL multimers by total VWF antigen (VWF:Ag) levels, calculated as VWF:Ag x VWF:S, VWF:Ag x VWF:M and VWF:Ag x VWF:L, respectively.
Results: Disposition kinetics of VWF:Ag x VWF:S, VWF:Ag x VWF:M and VWF:Ag x VWF:L were best described by two-compartment models. Endogenous levels were accounted for as a constant background. PK model predictions showed that L/UL multimers had the highest degree of similarity in terms of disposition kinetics, indicated by a near-parallel PK curve to VWF:RCo, whereas S and M multimer fractions were characterized by a slower PK profile
Conclusions: This model-based analysis provides supporting evidence that the VWF:RCo activity in patients with severe VWD is associated with the persistence of L/UL VWF multimers in systemic circulation.
To cite this abstract in AMA style:Bauer A, Smania G, Friberg-Hietala S, Ploder B, Mellgård B, Wolfsegger M. Investigating the Relationship between VWF Multimeric Pattern and VWF: RCo Activity through Population PK Modeling in Patients with Severe VWD Treated with Recombinant VWF [abstract]. Res Pract Thromb Haemost. 2020; 4 (Suppl 1). https://abstracts.isth.org/abstract/investigating-the-relationship-between-vwf-multimeric-pattern-and-vwf-rco-activity-through-population-pk-modeling-in-patients-with-severe-vwd-treated-with-recombinant-vwf/. Accessed November 30, 2020.
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