Pharmacogenetics in pediatrics. Implications for practice

Abstract

Cumulative experience with pharmacotherapy in children indicates that it is difficult to prescribe medications rationally solely on the basis of patient age. Furthermore, the apparent drug biotransformation phenotype may be influenced by disease (e.g., infection), environmental factors (e.g., diet and environmental contaminants), and concurrent medications. Therefore, characterization of drug biotransformation pathways during development and, at a given developmental stage, the effects of known modulators of drug biotransformation are essential for optimum treatment. This is particularly true when one considers that altered drug biotransformation may contribute significantly to therapeutic failure (e.g., graft rejection with inadequate serum and tissue concentrations of cyclosporin and myelotoxicity consequent to a relative inability to metabolize normal doses of certain antineoplastic agents). Accordingly, the goals of coordinated clinical and basic investigations should be to characterize important drug biotransformation pathways for compounds under development and intended for use in pediatrics and to identify the population extremes or "outliers" to aid in selection of an appropriate dosage range for efficacy studies. Acquired knowledge should then be incorporated into the drug-design process to further maximize the efficacy-toxicity ratio. The development of acceptable, preferably noninvasive, phenotyping procedures for all age ranges including neonates, infants, and older children is a major challenge for investigators but, if met, will be rewarded with improved pediatric pharmacotherapy.