Pharmacodynamic interaction models in pediatric anesthesia

Pharmacokinetic (PK) and pharmacodynamic (PD) models are important tools for summarizing drug dose, concentration, and effect relationships. Co-administration of drugs may alter PK and PD relationships. Traditional methods of evaluating PD interactions include using isoboles, shifts in dose-response curves, or interaction indices based on parameters of potency derived from separate monotherapy and combination therapy analyses. These methods provide an estimation of the magnitude of effect for dose or concentration combinations, but they do not inform us on the time course of that effect, or its associated variability. A better way to investigate PD interactions is to use modeling, and to take advantage of the benefits of population analyses. A population analysis is a statistical method in which a model describing the typical (or population) response, and the variability between individuals within that population, is developed. Models for monotherapy, derived using a population approach, can be combined and extended to incorporate PD interactions between two or more drugs. The purpose of this article was to provide a general road map for understanding and interpreting PD interaction models, including the 'response surface' models. Several types of response surface models exist, and here we review these with examples taken from the literature. We also consider current and future applications for this type of analysis for clinical anesthesia and pediatrics.