Pharmacogenetics in Clinical Pediatrics: Challenges and Strategies

Abstract

The use of genetic information to guide medication decisions holds great promise to improve therapeutic outcomes through increased efficacy and reduced adverse events. As in many areas of medicine, pediatric research and clinical implementation in pharmacogenetics lag behind corresponding adult discovery and clinical applications. In adults, genotype-guided clinical decision support for medications such as clopidogrel, warfarin and simvastatin are in use in some medical centers. However, research conducted in pediatric populations demonstrates that the models and practices developed in adults may be inaccurate in children, and some applications lack any pediatric research to guide clinical decisions. To account for additional factors introduced by developmental considerations in pediatric populations and provide pediatric patients with maximal benefit from genotype-guided therapy, the field will need to develop and employ creative solutions. In this article, we detail some concerns about research and clinical implementation of pharmacogenetics in pediatrics, and present potential mechanisms for addressing them.

Innovative Study Designs Optimizing Clinical Pharmacology Research in Infants and Children

“…Nevertheless, important pharmacogenetic differences may exist between adults and children. For example, variants for a drug transporter (SLCO1B1) were associated with decreased pravastatin concentrations in children, whereas these variants in adults are associated with increased pravastatin concentrations . These differences underscore that potential changes in gene expression, physiology, and disease processes may alter pharmacogenetic relationships in children compared with adults .…”

“…To facilitate the identification of gene‐drug interactions in children and translation of these interactions to clinical practice, it will be necessary to collect genomic information from children on a large scale . In addition to ethical considerations, the wide‐scale collection of biospecimens presents several logistic challenges.…”

“…Given the low prevalence of many pediatric diseases, collecting deidentified genetic and clinical data on an institution‐wide scale is a potentially transformative way to augment clinical pharmacology research in children. However, important ethical concerns should first be resolved, including the handling of incidental variants, implications of genetic findings for family members, and misattributed paternity …”

Age‐Related Changes in MicroRNA Expression and Pharmacogenes in Human Liver

“…Developmental changes in drug disposition create the need for age‐appropriate pharmacotherapy . Although there have been many approaches for estimating pediatric drug dosing (e.g., extrapolation from adult data), these approaches are not adequate for many children, particularly for the very young patients (infants vs. children) .…”

Drug metabolism for the paediatrician

“…Moreover, similar to underlying disease and co-medication, the interplay of age and genetics may prevent the extrapolation of adult pharmacogenetic data to children 44. For example, in children, age and body size are more important contributors to variation in warfarin disposition than are CYP2C9 and VKORC1 genetic variation 45 46.…”