Impact of developmental pharmacology on pediatric study design: overcoming the challenges.

The need to establish drug-dosing guidelines in children highlights the challenges associated with the development of phases I and II pediatric clinical trials. These challenges are the consequence of significant developmental changes that characterize childhood and adolescence and can affect drug absorption, binding, renal elimination, and, especially, metabolism. In addition, genetic polymorphism can contribute to the variations in the expression of activity for specific drug-metabolizing enzymes. These developmental and genetic variations in pharmacokinetics are the major determinants of drug exposure over time and are thus directly related to the safety, efficacy, and toxicity of a drug dose. Therefore, in the development of pediatric protocols and appropriate dosing in children, it is essential to develop a strategy for addressing the developmental variables that affect drug exposure and to incorporate them into study design.