Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia

Malte Selch Larsen; Rasmus Vestergaard Juul; Andreas Velsing Groth; Ulrika S.H. Simonsson; Annemarie T. Kristensen; Tom Knudsen; Henrik Agersø; Mads Kreilgaard

doi:10.1016/j.ejps.2018.01.035

Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia

Malte Selch Larsen^*, Rasmus Vestergaard Juul, Andreas Velsing Groth, Ulrika S.H. Simonsson, Annemarie T. Kristensen, Tom Knudsen, Henrik Agersø, Mads Kreilgaard

^*Corresponding author for this work

2 Citations (Scopus)

Abstract

Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and rFVIII in mice, rats, monkeys, and dogs using nonlinear mixed-effects modelling, accounting for inter-individual variability, nonlinear kinetics and covariate effects. Three scaling principles were applied to predict human PK: proportional scaling to body weight from single species, scaling with fixed theory-based allometric exponents from single species, and allometric interspecies scaling with estimated allometric coefficients and exponents. The plasma concentration-time profile of rFVIIa and rFVIII in mice, rats, monkeys and dogs were accurately described by the developed species-specific PK models, accounting for nonlinear kinetics and gender-specific difference in clearance for rFVIII. The predictive performance of the animal population PK models of rFVIIa and rFVIII revealed significant species-variation. The developed PK models of rFVIIa and rFVIII in monkeys and dogs along with allometric interspecies scaling revealed high predictive performance for human PK, and may promote rational decision-making in future first-in-human trials for rFVIIa and rFVIII variants.

Original language	English
Journal	European Journal of Pharmaceutical Sciences
Volume	115
Pages (from-to)	196-203
ISSN	0928-0987
DOIs	https://doi.org/10.1016/j.ejps.2018.01.035
Publication status	Published - 2018

Keywords

Allometric scaling
Coagulation factors
Interspecies
Pharmacokinetic modelling
Prediction

Access to Document

10.1016/j.ejps.2018.01.035

Cite this

Larsen, M. S., Juul, R. V., Groth, A. V., Simonsson, U. S. H., Kristensen, A. T., Knudsen, T., Agersø, H., & Kreilgaard, M. (2018). Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia. European Journal of Pharmaceutical Sciences, 115, 196-203. https://doi.org/10.1016/j.ejps.2018.01.035

Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia. / Larsen, Malte Selch; Juul, Rasmus Vestergaard; Groth, Andreas Velsing et al.

In: European Journal of Pharmaceutical Sciences, Vol. 115, 2018, p. 196-203.

Research output: Contribution to journal › Journal article › Research › peer-review

Larsen, MS, Juul, RV, Groth, AV, Simonsson, USH, Kristensen, AT, Knudsen, T, Agersø, H & Kreilgaard, M 2018, 'Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia', European Journal of Pharmaceutical Sciences, vol. 115, pp. 196-203. https://doi.org/10.1016/j.ejps.2018.01.035

@article{07660d335a3f4971a413e5804e64a23b,

title = "Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia",

abstract = "Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and rFVIII in mice, rats, monkeys, and dogs using nonlinear mixed-effects modelling, accounting for inter-individual variability, nonlinear kinetics and covariate effects. Three scaling principles were applied to predict human PK: proportional scaling to body weight from single species, scaling with fixed theory-based allometric exponents from single species, and allometric interspecies scaling with estimated allometric coefficients and exponents. The plasma concentration-time profile of rFVIIa and rFVIII in mice, rats, monkeys and dogs were accurately described by the developed species-specific PK models, accounting for nonlinear kinetics and gender-specific difference in clearance for rFVIII. The predictive performance of the animal population PK models of rFVIIa and rFVIII revealed significant species-variation. The developed PK models of rFVIIa and rFVIII in monkeys and dogs along with allometric interspecies scaling revealed high predictive performance for human PK, and may promote rational decision-making in future first-in-human trials for rFVIIa and rFVIII variants.",

keywords = "Allometric scaling, Coagulation factors, Interspecies, Pharmacokinetic modelling, Prediction",

author = "Larsen, {Malte Selch} and Juul, {Rasmus Vestergaard} and Groth, {Andreas Velsing} and Simonsson, {Ulrika S.H.} and Kristensen, {Annemarie T.} and Tom Knudsen and Henrik Agers{\o} and Mads Kreilgaard",

year = "2018",

doi = "10.1016/j.ejps.2018.01.035",

language = "English",

volume = "115",

pages = "196--203",

journal = "Norvegica Pharmaceutica Acta",

issn = "0928-0987",

publisher = "Elsevier",

}

TY - JOUR

T1 - Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia

AU - Larsen, Malte Selch

AU - Juul, Rasmus Vestergaard

AU - Groth, Andreas Velsing

AU - Simonsson, Ulrika S.H.

AU - Kristensen, Annemarie T.

AU - Knudsen, Tom

AU - Agersø, Henrik

AU - Kreilgaard, Mads

PY - 2018

Y1 - 2018

N2 - Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and rFVIII in mice, rats, monkeys, and dogs using nonlinear mixed-effects modelling, accounting for inter-individual variability, nonlinear kinetics and covariate effects. Three scaling principles were applied to predict human PK: proportional scaling to body weight from single species, scaling with fixed theory-based allometric exponents from single species, and allometric interspecies scaling with estimated allometric coefficients and exponents. The plasma concentration-time profile of rFVIIa and rFVIII in mice, rats, monkeys and dogs were accurately described by the developed species-specific PK models, accounting for nonlinear kinetics and gender-specific difference in clearance for rFVIII. The predictive performance of the animal population PK models of rFVIIa and rFVIII revealed significant species-variation. The developed PK models of rFVIIa and rFVIII in monkeys and dogs along with allometric interspecies scaling revealed high predictive performance for human PK, and may promote rational decision-making in future first-in-human trials for rFVIIa and rFVIII variants.

AB - Various experimental animal models are used in haemophilia research, however, little is known about how well the different species predict pharmacokinetic (PK) profiles in haemophilia patients. The aim of the current study was to describe the plasma concentration-time profile of recombinant activated factor VII (rFVIIa) and recombinant factor VIII (rFVIII) in several experimental animal models using population PK modelling, and apply a simulation-based approach to evaluate how well the developed animal population PK models predict human PK. PK models were developed for rFVIIa and rFVIII in mice, rats, monkeys, and dogs using nonlinear mixed-effects modelling, accounting for inter-individual variability, nonlinear kinetics and covariate effects. Three scaling principles were applied to predict human PK: proportional scaling to body weight from single species, scaling with fixed theory-based allometric exponents from single species, and allometric interspecies scaling with estimated allometric coefficients and exponents. The plasma concentration-time profile of rFVIIa and rFVIII in mice, rats, monkeys and dogs were accurately described by the developed species-specific PK models, accounting for nonlinear kinetics and gender-specific difference in clearance for rFVIII. The predictive performance of the animal population PK models of rFVIIa and rFVIII revealed significant species-variation. The developed PK models of rFVIIa and rFVIII in monkeys and dogs along with allometric interspecies scaling revealed high predictive performance for human PK, and may promote rational decision-making in future first-in-human trials for rFVIIa and rFVIII variants.

KW - Allometric scaling

KW - Coagulation factors

KW - Interspecies

KW - Pharmacokinetic modelling

KW - Prediction

U2 - 10.1016/j.ejps.2018.01.035

DO - 10.1016/j.ejps.2018.01.035

M3 - Journal article

C2 - 29369801

AN - SCOPUS:85040966899

SN - 0928-0987

VL - 115

SP - 196

EP - 203

JO - Norvegica Pharmaceutica Acta

JF - Norvegica Pharmaceutica Acta

ER -

Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia

Abstract

Keywords

Access to Document

Fingerprint

Cite this