Impact of capacity-limited binding on recombinant factor VIII and von Willebrand factor pharmacokinetics in hemophilia A rats
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Essentials Knowledge of the interplay between FVIII and VWF pharmacokinetics (PK) is lacking. We characterized the capacity-limited PK of FVIII and VWF. The PK model described the PK of FVIII and VWF over a broad range of rFVIII doses. High-dose rFVIII treatment can reduce the endogenous VWF levels. Background: Understanding of the pharmacokinetics (PK) interplay between factor VIII (FVIII) and von Willebrand factor (VWF) following high-dose FVIII treatment is lacking. Objectives: To 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. Methods: We 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. Results: The 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. Conclusions: We 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.
Original language | English |
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Journal | Journal of Thrombosis and Haemostasis |
Volume | 17 |
Issue number | 6 |
Pages (from-to) | 964-974 |
Number of pages | 11 |
ISSN | 1538-7933 |
DOIs | |
Publication status | Published - 2019 |
- capacity-limited pharmacokinetics, factor VIII, hemophilia A rat, pharmacokinetic modeling, von Willebrand factor
Research areas
ID: 226785744