Review
Special issue: Pharmacology in The Netherlands
Mechanism-based pharmacokinetic-pharmacodynamic (PK-PD) modeling in translational drug research

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The use of pharmacokinetic-pharmacodynamic (PK-PD) modeling in translational drug research is a promising approach that provides better understanding of drug efficacy and safety. It is applied to predict efficacy and safety in humans using in vitro bioassay and/or in vivo animal data. Current research in PK-PD modeling focuses on the development of mechanism-based models with improved extrapolation and prediction properties. A key element in mechanism-based PK-PD modeling is the explicit distinction between parameters for describing (i) drug-specific properties and (ii) biological system-specific properties. Mechanism-based PK-PD models contain specific expressions for the characterization of processes on the causal path between drug exposure and drug response. The different terms represent: target-site distribution, target binding and activation and transduction. Ultimately, mechanism-based PK-PD models will also characterize the interaction of the drug effect with disease processes and disease progression. In this review, the principles of mechanism-based PK-PD modeling are described and illustrated by recent applications.

Section snippets

Introduction – PK-PD modeling in translational drug research

Modern drug discovery and development is associated with high attrition rates exceeding 90%, which are mainly caused by lack of efficacy and/or unexpected safety concerns [1]. This raises the question of how to improve the prediction of drug efficacy and safety in humans on the basis of information from in vitro bioassays and/or in vivo animal studies.

In recent years, pharmacokinetic-pharmacodynamic (PK-PD) modeling has become a key success factor in modern drug discovery and development.

Translational pharmacology aims to predict features of drug exposure and drug response

Mechanism-based PK-PD modeling aims at the prediction of exposure–response relationships in humans, including their inherent intra- and inter-individual variability. Exposure is expressed as the time course of the drug concentration in plasma, whereas response is expressed as the time course of the drug-effect intensity.

Mechanism-based PK-PD models contain specific expressions to quantitatively characterize processes on the causal path between plasma concentration and effect, such as (i) drug

Target site distribution

Most drugs have their target site outside the plasma. Hence, distribution to the site of action might represent a rate-limiting step in the onset and the duration of the effect. This is often reflected in a delay, or ‘hysteresis’, of the pharmacological effect relative to the drug concentration in plasma. Also, steady-state drug concentrations in plasma might not adequately reflect concentrations at the site of action (i.e. the ‘biophase’).

The so-called ‘effect compartment model’ has been

Conclusion

PK-PD modeling has evolved from a descriptive discipline into a science with biological and mechanistic plausibility. Specifically, novel concepts of mechanism-based PK-PD modeling have been developed, which constitute a scientific basis for predicting drug effects in humans on the basis of information from pre-clinical in vitro and in vivo investigations. An important issue in this respect is the scaling of biological system-specific information between species. In initial investigations,

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