Quantitative structure–pharmacokinetic/pharmacodynamic relationships

Quantitative structure–activity relationships have long been considered a vital component of drug discovery and development, providing insight into the role of molecular properties in the biological activity of similar and unrelated compounds. Recognition that in vitro bioassay and/or pre-clinical activity are insufficient for anticipating which compounds are suitable leads for further development has shifted the focus toward integrated pharmacokinetic (PK) and pharmacodynamic (PD) processes. Over the last decade, considerable progress has been made in constructing empirical and mechanistic quantitative structure–PK relationships (QSPKR), as well as diverse mechanism-based pharmacodynamic models of drug effects. In this review, traditional and contemporary approaches to developing QSPKR models are discussed, along with selected examples of attempts to couple QSPKR and pharmacodynamic models to anticipate the intensity and time-course of the pharmacological effects of new or related compounds, or quantitative structure–pharmacodynamic relationships modeling. Such models are in accordance with the goals of systems biology and the ideal of designing drugs and delivery systems from first principles.