Pharmacogenetics in the Treatment of Congenital and Acquired Cardiac Disease During Childhood Jonathan Wagner Abstract As medicine moves closer to an era of precision-guided therapy, pharmacotherapy will be a cornerstone of this innovation Pharmacokinetics, pharmacodynamics, and pharmacogenomics are the instruments by which our field can execute precision-guided therapy for the individual pediatric patient Before genetic testing is performed for variants related to drug response, one must ensure that variable response is not secondary to poor systemic exposure Therefore a full review of the gene products that are quantitatively important in the drug's disposition (absorption, distribution, metabolism, excretion) must be reviewed and investigated Pediatricians are uniquely primed to understand these instruments owing to our experience with physiologic development and genetics Precision-guided pharmacotherapeutics is essential to improve the outcomes of congenital and acquired heart disease during childhood Keywords cytochrome p450; ontogeny; pharmacogenetics; pharmacogenomics; pharmacokinetics; transporters Introduction Pediatric cardiology providers commonly observe variable responses to cardiovascular pharmacotherapy and, as a result, inconsistent or counterintuitive outcomes in congenital and acquired heart disease The contribution of development and/or genetic variation to the observed variability in cardiovascular drug disposition and response in childhood requires further investigation and clarity In the absence of data that are applicable to the individual child, providers making clinical decisions must often rely on data generated in adults However, it is universally appreciated in our specialty that growth and development (ontogeny) can potentially influence the diagnosis and treatment of clinical disease during childhood Ontogeny is equally important when discussing pediatric drug disposition and response.1 Therefore, drawing the same conclusions or, potentially worse, extrapolating adult pharmacogenetic and/or pharmacogenomics data to the pediatric cohort must be performed with caution.2,3 Genetic variation is invariably associated with the pioneer efforts to deliver “precision medicine.”4 However, the provider must recognize that genetic variation remains only one patient-specific factors that may influence drug disposition and response The physiologic profile of the individual patient (e.g., Fontan circulation), formulation of the drug (e.g., tablet vs liquid preparation), and/or environmental factors (e.g., diet) must be taken into consideration when providing precision-guided therapy.5 Notwithstanding, for the purpose of this chapter, the primary emphasis will be on the influence of pharmacogenetics on the treatment and outcome of pediatric cardiovascular disease ... cytochrome p450; ontogeny; pharmacogenetics; pharmacogenomics; pharmacokinetics; transporters Introduction Pediatric cardiology providers commonly observe variable responses to cardiovascular pharmacotherapy and, as a result, inconsistent or counterintuitive... when discussing pediatric drug disposition and response.1 Therefore, drawing the same conclusions or, potentially worse, extrapolating adult pharmacogenetic and/or pharmacogenomics data to the pediatric cohort must be performed with... Pharmacokinetics, pharmacodynamics, and pharmacogenomics are the instruments by which our field can execute precision-guided therapy for the individual pediatric patient Before genetic testing is performed for variants related to drug response, one must ensure that variable response is not