Mager2005 - Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition

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Model Identifier
BIOMD0000000765
Short description 
This model was developed with the aim of constructing an equilibrium model of the pharmacokinetic behaviour of a drug exhibiting target-mediated drug disposition (TMDD). TMDD involves the inclusion of drug-target interactions within a pharmacokinetic description, something which is usually considered negligible and subsequently excluded. Two approaches were used, one of which involved a quasi-equilibrium method to describe the kinetics of TMDD.
Format
SBML (L2V4)
Related Publication
  • Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition.
  • Mager DE, Krzyzanski W
  • Pharmaceutical research , 10/ 2005 , Volume 22 , Issue 10 , pages: 1589-1596 , PubMed ID: 16180117
  • Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, 14260, USA.
  • The aim of this study is to derive and evaluate an equilibrium model of a previously developed general pharmacokinetic model for drugs exhibiting target-mediated drug disposition (TMDD).A quasi-equilibrium solution to the system of ordinary differential equations that describe the kinetics of TMDD was obtained. Computer simulations of the equilibrium model were carried out to generate plasma concentration-time profiles resulting from a large range of intravenous bolus doses. Additionally, the final model was fitted to previously published pharmacokinetic profiles of leukemia inhibitory factor (LIF), a cytokine that seems to exhibit TMDD, following intravenous administration of 12.5, 25, 100, 250, 500, or 750 microg/kg in sheep.Simulations show that pharmacokinetic profiles display steeper distribution phases for lower doses and similar terminal disposition phases, but with slight underestimation at early time points as theoretically expected. The final model well-described LIF pharmacokinetics, and the final parameters, which were estimated with relatively good precision, were in good agreement with literature values.An equilibrium model of TMDD is developed that recapitulates the essential features of the full general model and eliminates the need for estimating drug-binding microconstants that are often difficult or impossible to identify from typical in vivo pharmacokinetic data.
Contributors
Submitter of the first revision: Johannes Meyer
Submitter of this revision: Tung Nguyen
Modellers: Tung Nguyen, Johannes Meyer

Metadata information

is (2 statements)
BioModels Database MODEL1907290001
BioModels Database BIOMD0000000765

isDescribedBy (1 statement)
PubMed 16180117

isDerivedFrom (1 statement)
PubMed 11999290

hasTaxon (1 statement)
Taxonomy 1758

hasProperty (2 statements)
Mathematical Modelling Ontology Ordinary differential equation model
NCIt Pharmacokinetics

Curation status
Curated
Modelling approach(es)
ordinary differential equation model
Tags

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Model files
Mager2005.xml SBML L2V4 Representation of Mager2005 - Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition 45.32 KB Preview | Download

Additional files
Mager2005.cps COPASI file of Mager2005 - Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition 71.39 KB Preview | Download
Mager2005.sedml SED-ML file of Mager2005 - Quasi-equilibrium pharmacokinetic model for drugs exhibiting target-mediated drug disposition 1.73 KB Preview | Download

  • Model originally submitted by : Johannes Meyer
  • Submitted: Jul 29, 2019 12:21:24 PM
  • Last Modified: Oct 1, 2021 11:50:37 AM
Revisions
  • Version: 5 public model Download this version
    • Submitted on: Oct 1, 2021 11:50:37 AM
    • Submitted by: Tung Nguyen
    • With comment: Automatically added model identifier BIOMD0000000765
  • Version: 2 public model Download this version
    • Submitted on: Jul 29, 2019 12:21:24 PM
    • Submitted by: Johannes Meyer
    • With comment: Automatically added model identifier BIOMD0000000765

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

Legends
: Variable used inside SBML models


Species
Species Initial Concentration/Amount
A T

drug ; Tissue 		0.0 mmol
C

drug ; 7-Methylxanthine 		4000.0 mmol
RC

receptor complex 		0.0 mmol
R

Receptor 		53.0 mmol
Reactions
Reactions Rate Parameters
A_T => Peripheral_Tissue*k_tp*A_T k_tp = 0.0
=> R + C; RC Central*k_off*RC k_off = 0.1
R + C => RC Central*k_on*R*C k_on = 0.1
=> R Central*k_syn k_syn = 0.0
=> C; A_T k_tp*A_T/V_c k_tp = 0.0; V_c = 10.0
=> A_T; C k_pt*C*V_c k_pt = 0.0; V_c = 10.0
RC => Central*(k_off+k_int)*RC k_off = 0.1; k_int = 0.0
Curator's comment:
(added: 29 Jul 2019, 11:58:38, updated: 29 Jul 2019, 11:58:38)
Reproduced plot of Figure 2 Case A in the original publication, with an initial value of C(0) = 4000. Note that C_Tot (e.g. the drug plus drug-receptor complex) concentration was plotted. Model simulated and plot produced using COPASI 4.24 (Build 197).