A challenge model of TNFα turnover with LPS provocations and drug intervention

F. Held, E. Hoppe, M. Cvijovic, M. Jirstrand, J. Gabrielsson. In proceedings of the 28th PAGE meeting, Stockholm,Sweden, 11-14 June, 2019.


Tumor necrosis factor alpha (TNFα) is a pro-inflammatory cytokine associated with the pathogenesis of several immune-mediated diseases. Free TNFα is almost undetectable in blood of healthy organisms. Experimentally, the effect of inflammatory mediators is studied in-vivo after intravenous admini­stration of lipopolysaccharides (LPS), where the challenger causes a rapid but transient release of TNFα. Hence, the base line of the biomarker under study is vanishing and only a transient effect is available for quantifying the effect of drug intervention. This poses a challenging situation for assessing the pharmacodynamic effect by exploratory data analysis and modeling of experimental data [1]. The objectives of this work were to

  • Demonstrate how to assess a pharmacodynamic effect represented by a biomarker with a baseline below the limit of detection.
  • Demonstrate how exploratory data analysis may provide guidance in formulating a model, which enables a better understanding of target biology.

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