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CPT Pharmacometrics Syst Pharmacol. 2014 Jan 8;3:e89. doi: 10.1038/psp.2013.64.

A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development.

Author information

1
The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.
2
Biotherapeutics Clinical Research, Pfizer Inc, Cambridge, Massachusetts, USA.
3
Immunoscience, Pfizer Inc, Cambridge, Massachusetts, USA.
4
Global Clinical Pharmacology, Pfizer Inc, Cambridge, Massachusetts, USA.
5
Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc, Cambridge, Massachusetts, USA.
6
Quantitative Clinical Sciences, Biotherapeutics, Pfizer Inc, Cambridge, Massachusetts, USA.

Abstract

In this study, we have developed a multiscale systems model of interleukin (IL)-6-mediated immune regulation in Crohn's disease, by integrating intracellular signaling with organ-level dynamics of pharmacological markers underlying the disease. This model was linked to a general pharmacokinetic model for therapeutic monoclonal antibodies and used to comparatively study various biotherapeutic strategies targeting IL-6-mediated signaling in Crohn's disease. Our work illustrates techniques to develop mechanistic models of disease biology to study drug-system interaction. Despite a sparse training data set, predictions of the model were qualitatively validated by clinical biomarker data from a pilot trial with tocilizumab. Model-based analysis suggests that strategies targeting IL-6, IL-6Rα, or the IL-6/sIL-6Rα complex are less effective at suppressing pharmacological markers of Crohn's than dual targeting the IL-6/sIL-6Rα complex in addition to IL-6 or IL-6Rα. The potential value of multiscale system pharmacology modeling in drug discovery and development is also discussed.CPT: Pharmacometrics & Systems Pharmacology (2014) 3, e89; doi:10.1038/psp.2013.64; advance online publication 8 January 2014.

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