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- W75804964 abstract "In recent years pharmacokinetic/pharmacodynamic (PK/PD) modeling has developed as an independent scientific discipline, aiming at the prediction of the time course of drug effect in vivo. PK/PD modeling is already widely applied in drug development for optimization of the dosing and delivery of novel drugs in phase II/III clinical trials. In the meantime however PK/PD modeling is increasingly also applied in preclinical investigations. Here the objective is the prediction of the PK/PD properties of novel drugs in humans on the basis of information from in vitro bioassays and in vivo animal studies with the aim of improving lead optimization and drug candidate selection. The pertinent PK/PD information is subsequently used to optimize the design of early clinical trials. PK/PD modeling is biological systems analysis, whereby the time course of the drug effect is described mathematically on the basis of a set of drug specific and biological system specific parameters. Drug specific parameters (i.e., receptor affinity, intrinsic efficacy) characterize the interaction of the drug with the biological system and can in principle be estimated in in vitro bioassays. In contrast system specific parameters characterize the functioning of the integral biological system and can only be estimated in in vivo investigations. Mechanism-based PK/PD models contain specific expressions for processes on the causal path between drug administration and effect. These include (1) target site distribution, (2) target binding and activation, (3) transduction, and (4) the effect of homeostatic feedback mechanisms. Thereby effects on (5) disease processes are also considered. Mechanism-based PK/PD modeling relies on the use of biomarkers and pharmacodynamic endpoints, which characterize in a strictly quantitative manner processes on the causal path. In this chapter a general overview of the concepts of mechanism-based PK/PD modeling is presented. Subsequently the utility of PK/PD modeling in drug design and lead optimization is illustrated on the basis of recent research on the PK/PD correlations of adenosine A 1 receptor agonists, μ opioid receptor agonists, GABA A receptor agonists, serotonin 5HT 1A receptor agonists, and drug-induced QT interval prolongation. In the discussion of these examples the emphasis is on the prediction, in strictly quantitative manner, of in vivo drug effects in humans on the basis of information from (high-throughput) in vitro bioassays and in vivo animal studies." @default.
- W75804964 created "2016-06-24" @default.
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- W75804964 date "2007-01-01" @default.
- W75804964 modified "2023-09-25" @default.
- W75804964 title "Mechanism-Based Pharmacokinetic–Pharmacodynamic Modeling for the Prediction of In Vivo Drug Concentration–Effect Relationships – Application in Drug Candidate Selection and Lead Optimization" @default.
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