Journal of Pharmacokinetics and Pharmacodynamics

, Volume 28, Issue 6, pp 507–532 | Cite as

General Pharmacokinetic Model for Drugs Exhibiting Target-Mediated Drug Disposition

  • Donald E. Mager
  • William J. Jusko

Abstract

Drugs that bind with high affinity and to a significant extent (relative to dose) to a pharmacologic target such as an enzyme, receptor, or transporter may exhibit nonlinear pharmacokinetic (PK) behavior. Processes such as receptor-mediated endocytosis may result in drug elimination. A general PK model for characterizing such behavior is described and explored through computer simulations and applications to several therapeutic agents. Simulations show that model predicted plasma concentration vs. time profiles are expected to be polyexponential with steeper distribution phases for lower doses and similar terminal disposition phases. Noncompartmental parameters always show apparent Vss and CLD decreasing with dose, but apparent clearance decreases only when the binding process produces drug elimination. The proposed model well captured the time-course of drug concentrations for the aldose reductase inhibitor imirestat, the endothelin receptor antagonist bosentan, and recombinant human interferon-β 1a. This type of model has a mechanistic basis and considerable utility for fully describing the kinetics for various doses of relevant drugs.

target-mediated drug disposition nonlinear pharmacokinetics imirestat bosentan interferon-β receptor binding receptor-mediated endocytosis mathematical modeling human 

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Copyright information

© Plenum Publishing Corporation 2001

Authors and Affiliations

  • Donald E. Mager
    • 1
  • William J. Jusko
    • 1
  1. 1.Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical SciencesUniversity at Buffalo, State University of New YorkBuffalo

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