Mechanism-based pharmacokinetic-pharmacodynamic modeling: biophase distribution, receptor theory, and dynamical systems analysis

Publication Type:

Journal Article

Authors:

Danhof, M.; de Jongh, J.; De Lange, E.C.; Della Pasqua, O.; Ploeger, B.A.; Voskuyl, R.A.

Source:

Annu Rev Pharmacol Toxicol, Volume 47, p.357-400 (2007)

ISBN:

0362-1642 (Print)

DOI Name (links to online publication)

10.1146/annurev.pharmtox.47.120505.105154

Keywords:

Drug Delivery Systems; *Drug Design; Humans; *Models; Biological; *Pharmacokinetics; Pharmacology/*methods; Predictive Value of Tests; Receptors; Cell Surface/drug effects/physiology; Tissue Distribution

Abstract:

Mechanism-based PK-PD models differ from conventional PK-PD models in that they contain specific expressions to characterize, in a quantitative manner, processes on the causal path between drug administration and effect. This includes target site distribution, target binding and activation, pharmacodynamic interactions, transduction, and homeostatic feedback mechanisms. As the final step, the effects on disease processes and disease progression are considered. Particularly through the incorporation of concepts from receptor theory and dynamical systems analysis, important progress has been made in the field of mechanism-based PK-PD modeling. This has yielded models with much-improved properties for extrapolation and prediction. These models constitute a theoretical basis for rational drug discovery and development.