Dwivedi2014 - Healthy Volunteer IL6 Model

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Short description
Dwivedi2014 - Healthy Volunteer IL6 Model
This model is comprised of four models:
Possible avenues for Interleukin-6 (IL-6) inhibition in treating Crohn's disease are compared here. Each model refers to separate ligands. The system simulates differential activity of the ligands on the signalling of IL-6. This affects Signal Transducer and Activator of Transcription 3 (STAT3) activity on the production of biomarker C-Reactive Protein (CRP) expression.
Figures referring to this Healthy Volunteer model are 2c and 2d.

This model is described in the article:

Dwivedi G, Fitz L, Hegen M, Martin SW, Harrold J, Heatherington A, Li C.
CPT Pharmacometrics Syst Pharmacol 2014; 3: e89

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-6R?, or the IL-6/sIL-6R? complex are less effective at suppressing pharmacological markers of Crohn's than dual targeting the IL-6/sIL-6R? complex in addition to IL-6 or IL-6R?. 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.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V4)
Related Publication
  • A multiscale model of interleukin-6-mediated immune regulation in Crohn's disease and its application in drug discovery and development.
  • Dwivedi G, Fitz L, Hegen M, Martin SW, Harrold J, Heatherington A, Li C
  • CPT: pharmacometrics & systems pharmacology , 0/ 2014 , Volume 3 , pages: e89
  • The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia, USA.
  • 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.
Contributors
Vincent Knight-Schrijver

Metadata information

is
BioModels Database MODEL1408050000
BioModels Database BIOMD0000000534
isDescribedBy
PubMed 24402116
hasTaxon
Taxonomy Homo sapiens
hasPart
Gene Ontology JAK-STAT cascade
isVersionOf
hasVersion
Human Disease Ontology Crohn's disease
isPartOf
Reactome REACT_27307.1
Curation status
Curated
  • Model originally submitted by : Vincent Knight-Schrijver
  • Submitted: Aug 5, 2014 1:41:04 PM
  • Last Modified: Nov 4, 2016 2:41:08 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Nov 4, 2016 2:41:08 PM
    • Submitted by: Vincent Knight-Schrijver
    • With comment: Current version of Dwivedi2014 - Healthy Volunteer IL6 Model
  • Version: 1 public model Download this version
    • Submitted on: Aug 5, 2014 1:41:04 PM
    • Submitted by: Vincent Knight-Schrijver
    • With comment: Original import of Dwivedi2014 - Healthy Volunteer IL6 Model
Curator's comment:
(added: 05 Aug 2014, 17:23:59, updated: 05 Aug 2014, 17:23:59)
Figure 2c: Concentration of serum antibody with monthly (672 hours) dose regimen for three doses, 10 mg, 100 mg and 500 mg. Simulated using a parameter scan for Dose between 10 and 500 with 2 logarithmic intervals. Figure 2d: Concentration of antibody in serum, liver and gut compartments with monthly (672 h) dose regimen. A dose of 100 mg was used. Simulated using a Time Course for 2688 h (16 weeks).