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Pharmaceutical Research

, Volume 22, Issue 10, pp 1589–1596 | Cite as

Quasi-Equilibrium Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition

  • Donald E. Mager
  • Wojciech KrzyzanskiEmail author
Research Paper

Purpose

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).

Methods

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 μg/kg in sheep.

Results

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.

Conclusions

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.

Key Words

leukemia inhibitory factor mathematical model nonlinear pharmacokinetics target-mediated drug disposition 

Notes

Acknowledgments

The authors would like to thank Dr. S. A. Charman, Dr. C. J. H. Porter, and Dr. A. M. Segrave for providing the LIF PK data. This study was funded in part by Grant 57980 from the National Institute of General Medical Sciences, National Institutes of Health (for W. K.) and start-up funds (to D. E. M.) from the University at Buffalo, State University of New York.

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Copyright information

© Springer Science + Business Media, Inc. 2005

Authors and Affiliations

  1. 1.Department of Pharmaceutical SciencesUniversity at Buffalo, State University of New YorkBuffaloUSA

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