Role of Inflammatory Biomarkers in Establishing PK/PD Relationships and Target Organ Toxicity
Pp. 81-96 (16)
Sivaram Pillarisetti and Ish Khanna
High levels of inflammatory cytokines and adhesion molecules are associated with many inflammatory disorders [e.g. rheumatoid arthritis, inflammatory bowel disease and lupus] as well as metabolic and cardiovascular diseases including diabetes and obesity. Examples of such markers include tumor necrosis factor [TNFα], interleukins [IL-1, IL-6, IL-8 and IL-18], vascular cell adhesion molecules and markers of macrophage inflammation [e.g. MMPs]. In many preclinical disease models, levels of these markers are significantly elevated relative to normal animals. Modulation of these biomarkers with pharmaceutical agents in preclinical and clinical studies can be effectively used for concept validation, effective dose selection, and establishing good pharmacokinetics/pharcodynamics correlation. On the other hand, elevation of these markers in normal animals, following treatment with an agent, could indicate safety concerns leading to potential tissue damage. Monitoring of inflammatory markers in normal animals can be diagnostic and of high value in evaluating safety or efficacy of new molecules. The levels of biomarkers can be monitored either by high throughput microarrays/proteomics or by specific ELISA based assays. Since many of the biomarkers appear in systemic circulation, these can be monitored in blood/plasma without interference with tissues. This makes the approach particularly attractive for clinical studies. An overview of the biomarkers, potential applications and case histories linking biomarkers to PK/PD correlation from preclinical and clinical studies are discussed.
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