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Prediction of human pharmacokinetics of activated recombinant factor VII and B-domain truncated factor VIII from animal population pharmacokinetic models of haemophilia
Novo Nordisk AS, Global Res, Haemophilia Res, Haemophilia PK & ADME, Malov, Denmark.;Univ Copenhagen, Dept Vet Clin Sci, Frederiksberg, Denmark..
Novo Nordisk AS, Quantitat Clin Pharmacol, Soborg, Denmark..
Novo Nordisk AS, Quantitat Clin Pharmacol, Soborg, Denmark..
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmaceutical Biosciences.
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2018 (English)In: European Journal of Pharmaceutical Sciences, ISSN 0928-0987, E-ISSN 1879-0720, Vol. 115, p. 196-203Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV , 2018. Vol. 115, p. 196-203
Keywords [en]
Allometric scaling, Coagulation factors, Pharmacokinetic modelling, Interspecies, Prediction
National Category
Cardiac and Cardiovascular Systems
Identifiers
URN: urn:nbn:se:uu:diva-350745DOI: 10.1016/j.ejps.2018.01.035ISI: 000426993800022PubMedID: 29369801OAI: oai:DiVA.org:uu-350745DiVA, id: diva2:1206110
Available from: 2018-05-16 Created: 2018-05-16 Last updated: 2018-05-16Bibliographically approved

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Simonsson, Ulrika S H

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