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Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody

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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

Curation status
Curated
  • Model originally submitted by : Vincent Knight-Schrijver
  • Submitted: Aug 5, 2014 1:46:06 PM
  • Last Modified: Jan 13, 2017 4:03:17 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: Jan 13, 2017 4:03:17 PM
    • Submitted by: Vincent Knight-Schrijver
    • With comment: Current version of Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody
  • Version: 1 public model Download this version
    • Submitted on: Aug 5, 2014 1:46:06 PM
    • Submitted by: Vincent Knight-Schrijver
    • With comment: Original import of Dwivedi2014 - Crohns IL6 Disease model - Anti-IL6R Antibody
Curator's comment:
(added: 06 Aug 2014, 16:42:23, updated: 06 Aug 2014, 16:42:23)
Figure 3a: Reduction of CRP from baseline with administration of Tocilizumab, an anti IL6-R antibody. Doses of 560 mg every 2 weeks and 4 weeks were simulated. Simulated as two time courses, 2 weeks and 4 weeks. The antibody Kd was matched to Tocilizumab for this case (1 nmol/l). Figure 4d: Concentration of serum IL6, gut IL6 serum CRP and Gut pSTAT3 with a monthly (672 h) 300 mg dose regimen of IL6-R antibody. Simulated as a Time Course for 2016 h. Figure 4e: Suppression of CRP by IL6-R antibody after 12 weeks of monthly (672 h) doses. Three separate Kd values were assessed: 2.5, 25 and 250 pmol/l. Simulated with a two-paramater scan for Dose and Kd, Plotted using LibreCalc. Figure 4f: IL6-R antibody concentration in serum for 200 and 500 mg doses administered monthly (672 hours). Simulated as a parameter scan for Dose between 200 and 500 with 1 interval. Figure 5b: Suppression of CRP after 12 weeks of varied monthly (672 hours) doses. This simulation includes binding of the antibody to the ligand-receptor complex. Three separate Kd values were assessed: 2.5, 25 and 250 pmol/l. Simulated with a two-paramater scan for Dose and Kd, Plotted using LibreCalc