New Equilibrium Models of Drug-Receptor Interactions Derived from Target-Mediated Drug Disposition

The AAPS Journal
Lambertus A Peletier, Johan Gabrielsson

Abstract

In vivo analyses of pharmacological data are traditionally based on a closed system approach not incorporating turnover of target and ligand-target kinetics, but mainly focussing on ligand-target binding properties. This study incorporates information about target and ligand-target kinetics parallel to binding. In a previous paper, steady-state relationships between target- and ligand-target complex versus ligand exposure were derived and a new expression of in vivo potency was derived for a circulating target. This communication is extending the equilibrium relationships and in vivo potency expression for (i) two separate targets competing for one ligand, (ii) two different ligands competing for a single target and (iii) a single ligand-target interaction located in tissue. The derived expressions of the in vivo potencies will be useful both in drug-related discovery projects and mechanistic studies. The equilibrium states of two targets and one ligand may have implications in safety assessment, whilst the equilibrium states of two competing ligands for one target may cast light on when pharmacodynamic drug-drug interactions are important. The proposed equilibrium expressions for a peripherally located target may also be usefu...Continue Reading

References

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Jan 12, 2017·Journal of Pharmacokinetics and Pharmacodynamics·Gilbert KochJohannes Schropp
Jan 12, 2017·Journal of Pharmacokinetics and Pharmacodynamics·Gilbert KochJohannes Schropp
Feb 2, 2017·The AAPS Journal·Johan Gabrielsson, Lambertus A Peletier
Jul 21, 2017·Journal of Pharmacokinetics and Pharmacodynamics·Leonid Gibiansky, Ekaterina Gibiansky
Oct 13, 2017·Pharmacology & Therapeutics·Johan GabrielssonStephan Hjorth

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Citations

Nov 28, 2018·CPT: Pharmacometrics & Systems Pharmacology·Johannes SchroppGilbert Koch
Feb 10, 2021·Journal of Pharmacokinetics and Pharmacodynamics·Begum AlaybeyogluAndrew M Stein

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