Second-generation TNFα turnover model for improved analysis of test compound interventions in LPS challenge studies
Journal article, 2021

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.


Non-linear mixed effects

Sprague-Dawley rats

Turnover models

LPS challenge studies

Tumor necrosis factor alpha


Julia Larsson

Chalmers, Mathematical Sciences, Applied Mathematics and Statistics

Fraunhofer-Chalmers Centre

Edmund Hoppe

Grünenthal GmbH

Michael Gautrois

Grünenthal GmbH

Marija Cvijovic

Chalmers, Mathematical Sciences, Applied Mathematics and Statistics

University of Gothenburg

Mats Jirstrand

Fraunhofer-Chalmers Centre

European Journal of Pharmaceutical Sciences

0928-0987 (ISSN) 1879-0720 (eISSN)

Vol. 165 105937

Subject Categories

Pharmaceutical Sciences

Bioinformatics (Computational Biology)

Probability Theory and Statistics





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