Pharmacogenomics and Pharmacoepigenomics in Pediatric Medicine

Abstract

In the past several years, human genetics studies have progressed from monogenic to complex and common diseases because of the advancement in technologies. There is increased knowledge of the pharmacokinetics and pharmacogenomics of the drugs in adults as well as in children. These technological developments provided new diagnostic, prognostic, and therapeutic opportunities. We are now in a position to address many additional ambitious questions. For instance, in clinical medicine, interindividual variation in drug response is a major problem. Some of the heterogeneity of drug safety and efficacy among individuals can be explained by pharmacogenomics. It has also the potential to improve the treatment in both adults and children. In pediatrics however, there is ontogeny and metabolic capacity in children is different compared to adults. Several specific developmental changes may underlie some of the variability in drug response seen in children. They may also be responsible for adverse drug reactions (ADRs). Therefore, much of the diversity in drug effects cannot be explained by studying the genomic diversity alone. It is necessary to include the effect of growth (involves variations in gene expression) along with genetic differences when explaining the variability in treatment response. In this respect epigenomics may expand the scope of pharmacogenomics towards optimization of drug therapy. Future studies must focus on periods of maturation of the drug-metabolizing enzymes and polymorphisms in their genes by using candidate gene approach, gene expression analysis, genome-wide haplotype mapping, and proteomics. The integration of genetic data and clinical phenotypes along with the role of other factors is necessary to evaluate both efficacy and ADRs of any drug. It may require extensive genetic epidemiological studies spanning over many years.

Analysis of CYP2C19 Genetic Polymorphism in a Large Ethnic Hakka Population in Southern China

“…Advances in personalized medicine have been notable, as the role of inheritance in variable drug response are being unraveled and pharmacogenetics are being applied to develop individual-specific therapies. Inter-individual variability in drug dosage response or lack of response to a drug, as well as drug toxicity, can maximize drug efficacy and avoid adverse drug reactions and therapeutic failures [ 1 , 2 ]. The availability of genetic variation in genes encoding for drug metabolizing enzymes is a key element of individualized care.…”

Clinical Toxicology of OTC Cough and Cold Pediatric Medications: A Narrative Review

“…Although a variety of factors contribute to individual variances in medication response, there is solid evidence that genetic factors play a substantial role in drug response variability and toxicity. 43 Children and adults have different ontogeny and metabolic capacities. Several distinct developmental changes in children may account for the observed variations in drug responsiveness.…”

Ontogeny and the Application of Pharmacogenomics to Pediatric Drug Development

“…Other ADRs with a PGx link have clearly been identified in pediatric patients. Many of these ADRs have been identified in pediatric oncology and include hematopoietic effects with TPMT, peripheral neuropathy with vincristine because of CYP3A5 metabolism, and leukoencephalopathy with methotrexate because of methylenetetrahydrofolate reductase expression …”

“…Many of these ADRs have been identified in pediatric oncology and include hematopoietic effects with TPMT, peripheral neuropathy with vincristine because of CYP3A5 metabolism, and leukoencephalopathy with methotrexate because of methylenetetrahydrofolate reductase expression. 21 One additional consideration is the influence of PGx on drug interactions in pediatric patients. Although drug interactions are not studied directly in pediatric patients during drug development, tools such as physiologically based pharmacokinetics can be used to assess the importance of these interactions.…”