The need for modeling and simulation to design clinical investigations in children.

Recent legislation in the United States and Europe has resulted in an increased number of clinical trials of pharmaceutical agents in children. Creating a well-designed clinical trial that can be successfully completed is a challenging task, particularly as the study population includes younger and smaller children. Although there are some established principles for initially estimating appropriate doses of pharmaceutical agents in children based on known effective doses in adults, these rules are inadequate as the sole basis for designing a clinical trial in children. Factors such as maturation of metabolizing enzymes, relative physical maturation of the child, and altered absorption because of physiological differences in adults and children may contribute to alterations in the dose-exposure relationship. To account for the impact of these potential factors on a clinical trial, the use of modeling and simulation is necessary to anticipate the influence these variables can have on the desired clinical question to be addressed. The examples presented in this article highlight the principle that modeling and simulation is critical for adequately designing pediatrics trials.