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

Isabell Vargas Christensen; Mette Loftager; Frederik Rode; Hanne Mørck Nielsen; Mads Kreilgaard; Malte Selch Larsen

doi:10.1111/jth.14441

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

Isabell Vargas Christensen, Mette Loftager, Frederik Rode, Hanne Mørck Nielsen, Mads Kreilgaard, Malte Selch Larsen^*

^*Corresponding author for this work

1 Citation (Scopus)

Abstract

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 (K_ss = 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
Journal	Journal of Thrombosis and Haemostasis
Volume	17
Issue number	6
Pages (from-to)	964-974
Number of pages	11
ISSN	1538-7933
DOIs	https://doi.org/10.1111/jth.14441
Publication status	Published - 2019

Keywords

capacity-limited pharmacokinetics
factor VIII
hemophilia A rat
pharmacokinetic modeling
von Willebrand factor

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@article{3fc6ad0210204925b8f58ae93ee0d6c1,

title = "Impact of capacity-limited binding on recombinant factor VIII and von Willebrand factor pharmacokinetics in hemophilia A rats",

abstract = "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.",

keywords = "capacity-limited pharmacokinetics, factor VIII, hemophilia A rat, pharmacokinetic modeling, von Willebrand factor",

author = "{Vargas Christensen}, Isabell and Mette Loftager and Frederik Rode and {M{\o}rck Nielsen}, Hanne and Mads Kreilgaard and Larsen, {Malte Selch}",

year = "2019",

doi = "10.1111/jth.14441",

language = "English",

volume = "17",

pages = "964--974",

journal = "Journal of Thrombosis and Haemostasis",

issn = "1538-7933",

publisher = "Wiley-Blackwell",

number = "6",

}

TY - JOUR

T1 - Impact of capacity-limited binding on recombinant factor VIII and von Willebrand factor pharmacokinetics in hemophilia A rats

AU - Vargas Christensen, Isabell

AU - Loftager, Mette

AU - Rode, Frederik

AU - Mørck Nielsen, Hanne

AU - Kreilgaard, Mads

AU - Larsen, Malte Selch

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - capacity-limited pharmacokinetics

KW - factor VIII

KW - hemophilia A rat

KW - pharmacokinetic modeling

KW - von Willebrand factor

U2 - 10.1111/jth.14441

DO - 10.1111/jth.14441

M3 - Journal article

C2 - 30924607

AN - SCOPUS:85065654245

SN - 1538-7933

VL - 17

SP - 964

EP - 974

JO - Journal of Thrombosis and Haemostasis

JF - Journal of Thrombosis and Haemostasis

IS - 6

ER -

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

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Keywords

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