Pharmacokinetic–pharmacodynamic models that incorporate drug–target binding kinetics. (June 2019)

• Record Type: Journal Article
• Authors: Daryaee, Fereidoon; Tonge, Peter J
• Is Part Of: Current opinion in chemical biology. Volume 50(2019)
• Page Start: 120
• Page End: 127
• Publication Date: 2019-06
• Subjects: Bioorganic chemistry -- Periodicals; Biology -- Periodicals; Biochemistry -- Periodicals; Clinical biochemistry -- Periodicals; Biochemistry -- Periodicals; Chimie bio-organique -- Périodiques; Biologie -- Périodiques; 572.05
• DOI: 10.1016/j.cbpa.2019.03.008
• Languages: English
• ISSNs: 1367-5931

Abstract

Highlights: PK/PD models that integrate drug–target kinetics. Predictions of drug activity in the non-equilibrium environment of the human body. Inclusion of the rate of target turnover in modeling and generation of target vulnerability functions. 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 of kinetic selectivity in developing drugs for specific targets.