Impact of capacity‐limited binding on recombinant factor VIII and von Willebrand factor pharmacokinetics in hemophilia A rats

Abstract

Unlabelled Box BackgroundUnderstanding of the pharmacokinetics (PK) interplay between factor VIII (FVIII) and von Willebrand factor (VWF) following high‐dose FVIII treatment is lacking. ObjectivesTo characterize the PK of recombinant FVIII (rFVIII), VWF, and the rFVIII:VWF complex in hemophilia A rats following intravenous administration of rFVIII using PK modeling. A second aim was to investigate the effect of high daily dosing and constant expression of rFVIII on VWF exposure using PK simulations. MethodsWe developed a population PK model based on the principles of target‐mediated drug disposition modeling, using data on total rFVIII and VWF plasma concentrations, and the rFVIII:VWF complex luminescent oxygen channeling immunoassay signal in hemophilia A rats following intravenous administration of rFVIII (17.5, 100, 1000, and 5000 IU kg−1). Additionally, we evaluated the influence of high‐dose rFVIII treatment on the exposure of VWF using PK simulations. ResultsThe plasma concentration‐time profiles of total rFVIII and VWF, and the luminescent oxygen channeling immunoassay signal‐time profiles of the rFVIII:VWF complex were adequately described using a two‐compartment quasi‐steady‐state target‐mediated drug disposition model (Kss = 0.14 nmol L−1). The elimination half‐life of the rFVIII:VWF complex was dependent on the unbound plasma concentration of rFVIII. Additionally, we showed that high‐dose rFVIII treatment may significantly reduce the endogenous VWF levels. ConclusionsWe developed a population‐based PK model describing the time‐course of total rFVIII, total VWF, and the rFVIII:VWF complex over a broad range of rFVIII doses in hemophilia A rats.