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

This study presents a non-linear mixed effects model describing tumour necrosis factor alpha (TNF alpha) release after lipopolysaccharide (LPS) provocations in absence or presence of anti-inflammatory test compounds. Interoccasion variability and the pharmacokinetics of two test compounds have been added to this secondgeneration model, and the goal is to produce a framework of how to model TNF alpha 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 TNF alpha 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 TNF alpha response, respectively, and the potency of Test Compound A was estimated to 0.166 mu mol/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.