Pharmacokinetic-pharmacodynamic models that incorporate drug-target binding kinetics.

Pharmacokinetic-pharmacodynamic models that incorporate drug-target binding kinetics. Curr Opin Chem Biol. 2019 Apr 25;50:120-127 Authors: Daryaee F, Tonge PJ Abstract Pharmacokinetic/pharmacodynamic (PK/PD) models predict the effect time course resulting from a drug dose. In this review, we summarize the development of mechanistic PK/PD models that explicitly integrate the kinetics of drug-target interactions into predictions of drug activity. Such mechanistic models are expected to have several advantages over approaches in which concentration and effect are linked using variations of the Hill equation, and where preclinical data are often used as a starting point for modeling drug activity. Instead, explicit use of the full kinetic scheme for drug binding enables time-dependent changes in target occupancy to be calculated using the kinetics of drug-target interactions and drug PK, providing a more precise picture of target engagement and drug action in the non-equilibrium environment of the human body. The mechanistic PK/PD models also generate target vulnerability functions that link target occupancy and effect, and inform on the sensitivity of a target to engagement by a drug. Key factors such as the rate of target turnover can also be integrated into the modeling which, together with target vulnerability, provide additional information on the PK profile required to achieve the desired pharmacological effect and on the utility o...
Source: Current Opinion in Chemical Biology - Category: Biochemistry Authors: Tags: Curr Opin Chem Biol Source Type: research