Variability in the human drug response.

Variations in response to drugs may be pharmacodynamic, implying inter-individual differences in the response of receptors in equal concentrations of drug, or pharmacokinetic, implying that individuals receiving the same dose of drug will have different concentrations of drug in their body fluids. Either type of variation can be inherited or acquired. Variations in receptor sensitivity do occur but few instances, inherited or acquired, have well documented clinical relevance. If the dose response relationship for the drug in question is not steep, or if the therapeutic index is low, drug concentration in the region of the receptor will not be critical and causes of kinetic variation are unlikely to be clinically significant. However, it is the many causes of kinetic variation which are best described. These include effects due to drug formulation and changes in the absorption, distribution, metabolism and excretion of drugs. If a consideration of dynamics suggests that drug concentration will determine therapeutic efficacy, analysis and prediction of variability due to these factors is desirable. Prediction requires an accurate description of the system but commonly used pharmacokinetic models may fail when prediction is a goal. The variables, volume of distribution (Vd) and rate constant of elimination (Ke) are hybrid in that they arise from the interaction of patient and drug characteristics. Important events including macromolecular binding and altered blood flow may not be represented. More data is required to determine the clinical significance of pharmacodynamic variation but better analytical tools are required to deal with kinetic variation when this is important. Specifically, pharmacokinetic models should represent physiological variables and levels of unbound drug in body fluids should receive greater emphasis.