Second-generation TNFα turnover model for improved analysis of test compound interventions in LPS challenge studies
European Journal of Pharmaceutical Sciences, vol. 165, pp. 105937
Abstract
This study presents a non-linear mixed effects model describing tumour necrosis factor alpha (TNFα) release after lipopolysaccharide (LPS) provocations in absence or presence of anti-inflammatory test compounds. Inter-occasion variability and the pharmacokinetics of two test compounds have been added to this second-generation model, and the goal is to produce a framework of how to model TNFα response in LPS challenge studies in vivo and demonstrate its general applicability regardless of occasion or type of test compound. Model improvements based on experimental data were successfully implemented and provided a robust model for TNFα response after LPS provocation, as well as reliable estimates of the median pharmacodynamic parameters. The two test compounds, Test Compound A and roflumilast, showed 81.1% and 74.9% partial reduction of TNFα response, respectively, and the potency of Test Compound A was estimated to 0.166 µmol/L. Comparing this study with previously published work reveals that our model leads to biologically reasonable output, handles complex data pooled from different studies, and highlights the importance of accurately distinguishing the stimulatory effect of LPS from the inhibitory effect of the test compound.
Authors 5
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Julia Larsson corresponding
Fraunhofer Chalmers Research Centre for Industrial Mathematics · Chalmers University of Technology · University of Gothenburg
Affiliation as printed
Fraunhofer-Chalmers Centre, Chalmers Science Park, 412 88 Gothenburg, Sweden.; Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, 412 96 Gothenburg, Sweden.. Electronic address: julia.larsson@fcc.chalmers.se
Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, 412 96 Gothenburg, Sweden
Fraunhofer-Chalmers Centre, Chalmers Science Park, 412 88 Gothenburg, Sweden
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Affiliation as printed
Grünenthal GmbH, Aachen, Germany
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Affiliation as printed
Grünenthal GmbH, Aachen, Germany
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Chalmers University of Technology · University of Gothenburg
Affiliation as printed
Department of Mathematical Sciences, Chalmers University of Technology and University of Gothenburg, 412 96 Gothenburg, Sweden
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Fraunhofer Chalmers Research Centre for Industrial Mathematics
Affiliation as printed
Fraunhofer-Chalmers Centre, Chalmers Science Park, 412 88 Gothenburg, Sweden
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