Population PK/PD Analysis

Pharmacokinetics and pharmacodynamics are divisions of pharmacology that study the action of the body on the drug and the action of the drug on the body, respectively. They complete dose titration studies aimed to select rational dosage regimens. The classical pharmacokinetic (PK)/pharmacodynamic (PD) studies are experimental. They are usually performed on healthy volunteers or highly selected patients to minimize interindividual variability. These studies allow to demonstrate a mechanism and to obtain rough quantitative information on the link between the dose and the effect (PK/PD behavior) of the drug. Population PK/PD studies quantify the effect of the drug on a population of patients who could use the drug. They allow quantifying, explaining, and predicting how the variability of the drug plasma concentration acts on the variability of the drug effect. They enable optimization (individualization) of dosage regimen. Usually performed on a sample of patients who are representative of the target population, they can be considered as observational studies. Population PK/PD relies on the use of models. A model can be defined as a simplified description of reality. Most models used in population PK/PD are statistical models. These models describe observations (concentrations and effects), but may also give some outlines of the underlying biological process. This article focuses mainly on the modelling aspects of PK/PD analysis. First, we recall the definitions of pharmacokinetic, pharmacodynamic, PK/PD, and the population approach. The modelling approach is illustrated with the study of the curious toxic effect of topotecan, an anticancer drug. Simulations are then performed, by using estimates of the population parameters, to propose a dosage regimen with a controlled toxicity. DEFINITIONS