PHARMACOGENETICS IN CHILDREN

M. Schwab, M. Fischer-Bosch

Institute of Clinical Pharmacology, Stuttgart, Germany.

Appropriate dosing is a major problem in drug therapy not only in adults but also in children. Inherited differences in the metabolism and disposition of drugs and genetic polymorphisms affecting the targets of drug therapy (e.g. receptors) can have a pronounced influence on the efficacy and toxicity of medications. Such observations are summarized in the field of pharmacogenomics, whereas "pharmacogenetics" focused on inherited differences in drug metabolism and disposition. Pharmacogenetic factors are either rare gene defects or genetic polymorphisms which result in at least two phenotypes (and presumably at least two genotypes) exhibiting a frequency of more than 1%. Clinically, individuals can be classified by phenotyping as either poor-, extensive/rapid- or sometimes as ultra-rapid metabolizer. By means of molecular genetics allelic variants (e.g. mutation, deletion, amplification) can be detected which can affect protein function in comparison to wild-type. There is good evidence for some drug classes that polymorphic expression of metabolizing enzymes (e.g. N-acetyltransferase 2, cytochrome P450 1A2, 2C9, 2C19, 2D6, thiopurine methyltransferase) is responsible for either therapy failure, exaggerated drug response or serious toxicity after taking the "standard and safe" dose of medications. Whereas ethnic and racial diversity in the frequency of polymorphisms of drugmetabolizing enzymes are studied extensively, limited data are available concerning the expression of drug-metabolizing enzymes during development and ontogency. Additionally, information about the biochemical or physiological factors that modulate up-regulation and down-regulation of enzyme activity during development is also incomplete. Interindividual variability in drug metabolism in preterms, infants, toddlers and older children is the result of a complex interaction between pharmacogenetics, development, and additionally exogenous factors (e.g. disease, nutrition). Both pharmacogenetical and developmental factors affecting the activity of drug-metabolizing enzymes should be taken into account to improve pediatric pharmacotherapy that is to maximize the efficacy and to minimize toxicity of drugs.