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Related Experiment Videos

Target-mediated drug disposition and dynamics.

Donald E Mager1

  • 1Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, 543 Hochstetter Hall, Buffalo, NY 14260, USA. dmager@buffalo.edu

Biochemical Pharmacology
|February 14, 2006
PubMed
Summary
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Target-mediated drug disposition (TMDD) occurs when a drug binds strongly to its target, affecting its pharmacokinetics. Mathematical models can characterize TMDD and its pharmacodynamic implications, especially for new biotech drugs.

Area of Science:

  • Pharmacology
  • Biotechnology
  • Drug Development

Background:

  • Nonlinear pharmacokinetics and pharmacodynamics complicate drug characterization.
  • Target-mediated drug disposition (TMDD) involves high-affinity drug-target binding impacting drug properties.
  • TMDD is increasingly relevant for biotechnology pharmaceuticals.

Purpose of the Study:

  • To describe the fundamental principles of TMDD.
  • To discuss mathematical modeling approaches for characterizing TMDD.
  • To highlight the utility of integrated models for understanding drug-target interactions.

Main Methods:

  • Review of TMDD principles.
  • Discussion of mathematical modeling techniques.
  • Comparison of traditional PK/PD models with integrated mechanism-based TMDD models.

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Main Results:

  • TMDD can cause dose-dependent changes in pharmacokinetic parameters like clearance and volume of distribution.
  • Integrated TMDD models incorporate drug-target binding kinetics and stoichiometry.
  • These models allow inference of unobservable variables like drug-target complex density.

Conclusions:

  • TMDD is a critical consideration for drug development, particularly for biologics.
  • Mechanism-based TMDD models offer a robust framework for analyzing complex drug disposition.
  • Understanding TMDD is essential for predicting and interpreting pharmacodynamic effects.