Pharmacogenomics for Drug Dosing in Children: Current Use, Knowledge, and Gaps

Abstract

Pharmacogenomics research ranges from the discovery of genetic factors to explain interpatient variability in drug exposure and response to clinical implementation of this knowledge to improve pharmacotherapy. Medications with actionable pharmacogenomic associations are frequently used in children, and therefore pharmacogenomics-guided precision medicine is readily applicable to the pediatric population. Although heritable genetics are considered immutable, the impact of genetic variation in pharmacogenes is modified by other factors such as age-dependent changes in gene expression. Early evidence has emerged indicating that the interaction between ontogeny and pharmacogenomics determines whether or how genetics-based dosing algorithms should be adjusted in children versus adults. However, there is still a paucity of data describing pharmacogenomic associations in patient populations across the life span. Future research is much needed to evaluate the impact of pharmacogenomics on drug dosing specific to the pediatric population, along with consideration of other developmental and physiological factors uniquely related to drug disposition in this population.

Keywords: drug dosing; ontology; pediatrics; pharmacogenetics/pharmacogenomics; toxicology.

Figure:. Interaction of ontogeny with pharmacogenomics

This diagram demonstrates conceptually how both metabolizer status and changing gene/protein expression through different development stages lead to differences in drug concentrations achieved. The magnitude of differences between individuals predicted to be normal vs poor metabolizers by genotype is dependent on the relative expression of the gene at the development stage.