Basic concepts of pharmacokinetic/pharmacodynamic (PK/PD) modelling

Pharmacokinetic (PK) and pharmacodynamic (PD) information from the scientific basis of modern pharmacotherapy. Pharmacokinetics describes the drug concentration time courses in body fluids resulting from administration of a certain drug dose, pharmacodynamics the observed effect resulting from a certain drug concentration. The rationale for PK/PD-modelling is to link pharmacokinetics and pharmacodynamics in order to establish and evaluate dose-concentration-response relationships and subsequently describe and predict the effect-time courses resulting from a drug dose. Under pharmacokinetic steady-state conditions, concentration-effect relationships can be described by several relatively simple pharmacodynamic models, which comprise the fixed effect model, the linear model, the log-linear model, the E-max-model and the sigmoid E-max-model. Under non steady-state conditions, more complex integrated PK/PD-models are necessary to link and account for a possible temporal dissociation between the plasma concentration and the observed effect. Four basic attributes may be used to characterize PK/PD-models: First, the link between measured concentration and the pharmacologic response mechanism that mediates the observed effect, direct vs, indirect link; second, the response mechanism that mediates the observed effect, direct vs. indirect response; third, the information used to establish the link between measured concentration and observed effect, hard vs. soft link; and fourth, the time dependency of the involved pharmacodynamic parameters, time-variant vs. time-invariant. In general, PK/PD-modelling based on the underlying physiological process should be preferred whenever possible. The expanded use of PK/PD-modelling is assumed to be highly beneficial for drug development as well as applied pharmacotherapy and will most likely improve the current state of applied therapeutics.