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Eur J Pharm Sci. 2018 Mar 30;115:196-203. doi: 10.1016/j.ejps.2018.01.035. Epub 2018 Jan 31.

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

Author information

1
Haemophilia PK & ADME, Haemophilia Research, Global Research, Novo Nordisk A/S, Maaloev, Denmark; Department of Veterinary Clinical Sciences, University of Copenhagen, Frederiksberg, Denmark. Electronic address: xmtl@novonordisk.com.
2
Quantitative Clinical Pharmacology, Novo Nordisk A/S, Soeborg, Denmark.
3
Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
4
Department of Veterinary Clinical Sciences, University of Copenhagen, Frederiksberg, Denmark.
5
Translational Haemophilia Pharmacology, Haemophilia Pharmacology, Global Research, Novo Nordisk A/S, Maaloev, Denmark.
6
Haemophilia PK & ADME, Haemophilia Research, Global Research, Novo Nordisk A/S, Maaloev, Denmark.

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

PMID:
29369801
DOI:
10.1016/j.ejps.2018.01.035
[Indexed for MEDLINE]

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