Researchers have developed a novel population pharmacokinetics (PK) model of recombinant von Willebrand factor (rVWF) in patients with von Willebrand disease (VWD) or severe hemophilia A that appears to adequately predict platelet adhesion/aggregation and FVIII activity–time profiles following single and repeated intravenous rVWF dosing.
The study results were presented at the Thrombosis & Hemostasis Summit of North America (THSNA) 2020 Virtual Conference by Alexander Bauer of Baxalta Innovations GmbH, a Takeda company from Vienna, Austria, and colleagues at Shire US Inc and Baxalta US Inc (both are also Takeda companies) in Cambridge, Massachusetts, United States, and Pharmetheus AB, Uppsala, Sweden.
“An increased understanding of the effect of rVWF dosing, particularly the relationship between VWF:RCo and FVIII activity, could help with optimizing factor replacement therapy and personalizing treatment,” wrote the authors.
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To characterize the population PK of rVWF and predict effects in patients with VWD or hemophilia A, the team used individual patient PK data from 4 rVWF clinical studies (3 studies on VWD [ClinicalTrials.gov Identifiers: NCT00816660, NCT01410227, NCT02283268] and a phase 1 study in patients with severe hemophilia A) to develop the model.
Data from adult patients (≥18 years) were included in the study if they had no history or presence of VWF inhibitors or FVIII inhibitors (titer ≥0.6 Bethesda units). VWF:RCo and FVIII activity had been measured for up to 96 hours following rVWF infusion. A variety of covariates were also evaluated. The U.S. Food and Drug Administration and European Medicines Agency guidelines were followed for model selection and evaluation along with standard methods to assess model fit of the data.
In total, data from 79 patients who were treated with rVWF (median age, 35 years; range, 18 to 70 years), including 1664 VWF:RCo measurements, were used to build the model. More than half of the patients were men (58%), and the PK parameters were scaled to body weight (median, 74.0 kg; range, 44-145 kg).
Goodness of fit plots and visual predictive checks of the model showed no unacceptable trends, suggesting that this PK population model adequately captured VWF:RCo activity–time profiles for patients with VWD and severe hemophilia A who were receiving single and multiple dosing. No PK differences, aside from endogenous background VWF:RCo, were observed between patients with different VWD types or between patients with hemophilia A and VWD.
“This population PK model reasonably describes the PK of rVWF in patients with VWD or severe hemophilia A, and represents the first stage in the development of a population PK/pharmacodynamic (PD) model to describe and predict VWF:RCo and FVIII activity-time profiles following single and repeated intravenous rVWF dosing,” concluded the authors.
Disclosures: Authors include employees of Baxalta Innovations GmbH, a Takeda company (AB, BP, MW), an employee of Shire US Inc., a Takeda company (ZL), an employee of Baxalta US Inc., a Takeda company and a Takeda stock owner (BM), and an employee and co-owner of Pharmetheus AB (SF-H).
Reference
Bauer A, Ploder B, Li Z, Mellgård B, Friberg-Hietala S, Wolfsegger M. Population pharmacokinetics of recombinant von Willebrand factor in patients with von Willebrand disease or severe hemophilia A. Abstract presented at: THSNA 2020 Thrombosis & Hemostasis Summit of North America; October 27-30, 2020. Abstract 125.
