Predicting effective drug concentrations for individual patients - Determinants of pharmacodynamic variability

Variability in the relationship between pharmacological effect intensity and drug concentration (pharmacodynamics) is pronounced, usually exceeding pharmacokinetic variability. Whereas interindividual differences are large, intraindividual differences are much smaller, unless the individual experiences certain pathophysiological changes such as deterioration of renal function or progression of a chronic disease (for example, Parkinson's disease). Failure to appreciate the magnitude of interindividual variability in the pharmacodynamics of a drug can compromise fixed dose clinical trial outcomes, making the drug appear less effective or more toxic. In the face of pharmacodynamic variability it becomes important to identify useful predictors (covariates) of pharmacodynamic individuality to facilitate individually optimised pharmacotherapy. This requires clinical trial designs that incorporate extensive patient profiling, well beyond the usual short list of demographics (such as age, gender, race, bodyweight and smoking habits). In searching for predictors, it is helpful to appreciate the factors that may account for interindividual differences in the relationship between pharmacological effect intensity and drug concentration in plasma or other appropriate fluid. They include receptor density and affinity, the formation and elimination kinetics of endogenous ligands (such as the enkephalins), postreceptor transduction processes, homeostatic responses and the kinetic characteristics of transporters involved in drug transfer between fluids of distribution and the biophase. Correction of drug concentrations in plasma for protein binding, consideration of active and interactive metabolites, stereospecific assays and attention to drug distribution disequilibria are essential for successful identification of factors affecting pharmacodynamic variability. Pharmaceutical delivery systems (the 'hardware') must be combined with guidance for individualising drug dosage (the 'software' or user's manual) to provide for optimal and cost-effective pharmacotherapy.