Gabrielsson, Johan, Hjorth, Stephan, Vogg, Barbara, Harlfinger, Stephanie, Gutierrez, Pablo, Peletier, Lambertus, Pehrson, Rikard and Davidsson, Pia (2015) Modeling and Design of Challenge Tests: Inflammatory and Metabolic Biomarkers. Modeling and Design of Challenge Tests: Inflammatory and Metabolic Biomarkers .

Abstract

Given the complexity of pharmacological challenge experiments, it is perhaps not surprising that design, interpretation and communication of results from a quantitative point of view is relatively uncommon. Here we report an inventory of designs, the data they generate, and how this data is analyzed quantitatively. This range of data is typically obtained in drug discovery for anti-inflammatory, respiratory and metabolic diseases. Although we limit our analysis to these diseases, the challenge approach is generally applicable to the vast majority of pharmacological intervention. Using these methods we also try to draw inferences about future designs. We present five case studies in which models for pharmacodynamic effects of different therapeutic areas were applied to five typical designs. Plasma exposure to the test compounds was assayed by either liquid chromatography and mass spectrometry or ligand binding assays. To describe how drug intervention can regulate diverse processes, turnover models of test compound-challenger interaction, transduction processes, and biophase time courses were applied for biomarker response in eosinophil count, IL6 response, paw-swelling, TNFα response and glucose turnover in vivo.

Item Type:	Article
Keywords:	Mixture dynamics, turnover models, inhibitory drug action, lipopolysaccharide, Sephadex, eosinophils, LPS, IL6, IL1, paw-swelling, oral glucose tolerance test, hormetic concentration-response relationship
Date Deposited:	26 Apr 2016 23:45
Last Modified:	26 Apr 2016 23:45
URI:	https://oak.novartis.com/id/eprint/21436