Demin2013 - PKPD behaviour - 5-Lipoxygenase inhibitors

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Demin2013 - PKPD behaviour - 5-Lipoxygenase inhibitors

This model is described in the article:

Demin O, Karelina T, Svetlichniy D, Metelkin E, Speshilov G, Demin O Jr, Fairman D, van der Graaf PH, Agoram BM.
CPT Pharmacometrics Syst Pharmacol 2013; 2: e74

Abstract:

Zileuton, a 5-lipoxygenase (5LO) inhibitor, displays complex pharmaokinetic (PK)-pharmacodynamic (PD) behavior. Available clinical data indicate a lack of dose-bronchodilatory response during initial treatment, with a dose response developing after ~1-2 weeks. We developed a quantitative systems pharmacology (QSP) model to understand the mechanism behind this phenomenon. The model described the release, maturation, and trafficking of eosinophils into the airways, leukotriene synthesis by the 5LO enzyme, leukotriene signaling and bronchodilation, and the PK of zileuton. The model provided a plausible explanation for the two-phase bronchodilatory effect of zileuton-the short-term bronchodilation was due to leukotriene inhibition and the long-term bronchodilation was due to inflammatory cell infiltration blockade. The model also indicated that the theoretical maximum bronchodilation of both 5LO inhibition and leukotriene receptor blockade is likely similar. QSP modeling provided interesting insights into the effects of leukotriene modulation.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e74; doi:10.1038/psp.2013.49; advance online publication 11 September 2013.

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Format
SBML (L2V4)
Related Publication
  • Systems pharmacology models can be used to understand complex pharmacokinetic-pharmacodynamic behavior: an example using 5-lipoxygenase inhibitors.
  • Demin O, Karelina T, Svetlichniy D, Metelkin E, Speshilov G, Demin O Jr, Fairman D, van der Graaf PH, Agoram BM
  • CPT: pharmacometrics & systems pharmacology , 0/ 2013 , Volume 2 , pages: e74
  • Institute for Systems Biology SPb, Moscow, Russia.
  • Zileuton, a 5-lipoxygenase (5LO) inhibitor, displays complex pharmaokinetic (PK)-pharmacodynamic (PD) behavior. Available clinical data indicate a lack of dose-bronchodilatory response during initial treatment, with a dose response developing after ~1-2 weeks. We developed a quantitative systems pharmacology (QSP) model to understand the mechanism behind this phenomenon. The model described the release, maturation, and trafficking of eosinophils into the airways, leukotriene synthesis by the 5LO enzyme, leukotriene signaling and bronchodilation, and the PK of zileuton. The model provided a plausible explanation for the two-phase bronchodilatory effect of zileuton-the short-term bronchodilation was due to leukotriene inhibition and the long-term bronchodilation was due to inflammatory cell infiltration blockade. The model also indicated that the theoretical maximum bronchodilation of both 5LO inhibition and leukotriene receptor blockade is likely similar. QSP modeling provided interesting insights into the effects of leukotriene modulation.CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e74; doi:10.1038/psp.2013.49; advance online publication 11 September 2013.
Contributors
Vijayalakshmi Chelliah

Metadata information

is
BioModels Database MODEL1309160000
BioModels Database BIOMD0000000490
isDescribedBy
PubMed 24026253
isDerivedFrom
PubMed 22020181
PubMed 23146124
PubMed 21560018
hasTaxon
Taxonomy Homo sapiens
isVersionOf
hasProperty
Mathematical Modelling Ontology Ordinary differential equation model
hasVersion
Human Disease Ontology asthma
Curation status
Curated
  • Model originally submitted by : Vijayalakshmi Chelliah
  • Submitted: 16-Sep-2013 13:08:21
  • Last Modified: 17-Apr-2015 13:36:06
Revisions
  • Version: 2 public model Download this version
    • Submitted on: 17-Apr-2015 13:36:06
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Current version of Demin2013 - PKPD behaviour - 5-Lipoxygenase inhibitors
  • Version: 1 public model Download this version
    • Submitted on: 16-Sep-2013 13:08:21
    • Submitted by: Vijayalakshmi Chelliah
    • With comment: Original import of Demin2013 - PKPD behaviour - 5-Lipoxygenase inhibitors
Curator's comment:
(added: 04 Oct 2013, 13:33:55, updated: 04 Oct 2013, 13:33:55)
Figure 2 of the reference publication has been reproduced here. To simulate the curves of Figure 2, (i) set a=1 ("1" corresponds to multiple dose administration, "0" corresponds to single dose administration), (ii) set DOSE_zf to 400 or 600 (this corresponds to the dosage of Zileuton in mg), and (iii) set DOSE_ml to 10 or 50 (this corresponds to the dosage of Montelukast in mg). The model was simulated using Copasi v4.10 (Build 55) and the plots were generated using Gnuplot. The Copasi file corresponding to each of these four conditions (i.e.,DOSE_zf=400,600mg and DOSE_ml=10,50mg) that can be used to generate the plots, can be downloaded (see below).