Population Pharmacokinetic and Pharmacodynamic Methods

Abstract Pharmacokinetic and pharmacodynamic models are widely used to provide the quantitative basis for understanding the clinical pharmacology of pharmaceuticals. These models are used to describe both the average behavior in the population and differences between individuals. Pharmacokinetic models describe the time course of absorption, distribution, and elimination of a drug and any metabolites. Pharmacodynamic models describe the relationship between drug concentration and biological response. The pharmacokinetic‐pharmacodynamic model often has to account for a delay between the time course of concentrations and the time course of pharmacodynamic effect. Statistical models can describe the predictable and the unpredictable variability between and within subject variability in response. Predictable variability is most commonly understood for drug elimination processes and typically uses subject factors such as weight, renal function, and other medications to account for between subject differences. Unpredictable variability is usually larger than predictable variability. A wide variety of software has been developed for implementing these pharmacological and statistical models; of these, NONMEM (GloboMax LLC, Hanover, MD) is the most widely used. Newer algorithms are actively being developed. Model building and parameter estimation are often computationally intensive. Population models are used by drug developers to create a rationale framework for development, by regulatory health authorities to evaluate clinical trials and enhance product labels and by clinical researchers to understand human biology and disease progression.