title: A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development.
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.
authors.affiliation: The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.
authors.forename: G
authors.initials: G
authors.lastname: Dwivedi
authors.affiliation: Biotherapeutics Clinical Research, Pfizer Inc, Cambridge, Massachusetts, USA.
authors.forename: L
authors.initials: L
authors.lastname: Fitz
authors.affiliation: Immunoscience, Pfizer Inc, Cambridge, Massachusetts, USA.
authors.forename: M
authors.initials: M
authors.lastname: Hegen
authors.affiliation: Global Clinical Pharmacology, Pfizer Inc, Cambridge, Massachusetts, USA.
authors.forename: S W
authors.initials: SW
authors.lastname: Martin
authors.affiliation: Pharmacokinetics, Dynamics & Metabolism, Pfizer Inc, Cambridge, Massachusetts, USA.
authors.forename: J
authors.initials: J
authors.lastname: Harrold
authors.affiliation: Quantitative Clinical Sciences, Biotherapeutics, Pfizer Inc, Cambridge, Massachusetts, USA.
authors.forename: A
authors.initials: A
authors.lastname: Heatherington
authors.affiliation: Quantitative Clinical Sciences, Biotherapeutics, Pfizer Inc, Cambridge, Massachusetts, USA.
authors.forename: C
authors.initials: C
authors.lastname: Li