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 . 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.