Synopsis
The dose-exposure-response relationship for drugs may differ in pediatric patients compared to adults due to developmental changes in processes involved in drug disposition (absorption, distribution, metabolism and excretion) and drug response. This relative knowledge deficit has complicated drug efficacy and safety labeling of drugs for pediatric use. With the legislative changes that have occurred in the US and Europe over the last 20 years, many clinical studies have been conducted to establish drug dose-exposure relationships across the pediatric age spectrum from birth to adolescence. However, genetic variation has seldom been included in these investigations. This article applies a systematic approach to determine the relative contribution of development and genetic variation on drug disposition and response using HMG-CoA reductase inhibitors as a model. Application of the approach drives the collection of information relevant to understanding the potential contribution of ontogeny and genetic variation to statin dose-exposure-response in children, and identifies important knowledge deficits to be addressed through the design of future studies.