Clinical Pharmacogenetics in Pediatric Patients

Anwar Husain; Jennifer A. Loehle; David W. Hein

Disclosures

Pharmacogenomics. 2007;8(10):1403-1411. 

In This Article

Abstract and Introduction

Pediatric pharmacogenetic studies have the potential to improve the quality of medical care for children. The pediatric population presents a unique pharmacogenetic challenge as children have the additional complexity of ontological phenotypes that impact their drug response. Prescribing medications in children has historically been largely empirical, but utilization of pharmacogenetic information will allow pediatricians to gain key information regarding which patients are best suited for a particular therapeutic agent and which patients may be at risk for serious potentially life-threatening complications from standard treatment regimens. Although large, prospective, multisite investigators are still needed, we illustrate selective clinical examples of the pharmacogenetics for treatment of transplantation, asthma, leukemia and attention-deficit hyperactivity disorder in pediatric patients.

Human development stretches from prenatal phases to adolescence and represents a continuum of biological occurrences that allow the body to adapt, grow and eventually reproduce. Newborns and infants rapidly undergo simultaneous stages of organ growth and demonstrate large variability in drug response and metabolizing capabilities.[1,2] The enzymes, transporters and targets important for pediatric drugs all have the potential to vary along developmental timelines in terms of affinity, functional capacity and expression. Drug-metabolizing enzymes can vary according to chronological age.[3,4] Traditionally, dealing with these concerns clinically meant searching out patterns of drug response in relation to age in an empirical manner in order to determine the appropriate therapeutic agent and dose to administer in pediatric populations. Simplified dosing equations based on age and relative body size were used to calculate pediatric doses as clinicians made the assumption that predictable, linear relationships existed between mass and body surface area in infants, children, adolescents and adults. As an appreciation for ontogeny and its impact came about, normalization of drug dosing according to body weight or surface area largely replaced generic dosing equations. While adequate for short-term therapeutic regimens, the role of ontogeny becomes increasingly important as long-term therapeutic regimens are devised.[1,2]

Presently, pediatricians combine knowledge of clinical pharmacology, developmental physiology and professional experience in order to estimate the most accurate and effective drug-treatment plans for children. This imprecise determination process lacks power to predict absolute variability in pharmacokinetic and pharmacodynamic parameters. Wide variation in drug response among pediatric patients creates opportunities for either over- or under-dosing resulting in toxicity and loss of efficacy. Pediatric pharmacogenetic research has begun to reveal the elaborate interplay between genetics, ontogeny and drug response, helping provide pediatric patients with improved medical care.

A primary goal in pharmacogenetic research involves identifying variability in genes that affect drug response in order to individualize treatment strategies. A great number of gene products are involved in the absorption, distribution and action of drugs. Similarly, in human physiology an even greater number of genes work together to orchestrate the process of development. As a body matures it acquires defense mechanisms that provide protection against xenobiotics and infectious agents encountered in the environment. Patterns of gene expression, interactions between gene products and the role these factors play in the pathogenesis of pediatric diseases may only be relevant and detectable in children at specific age points. The molecules involved in a disease state are key targets for pharmacotherapeutic intervention. As such, determining gene expression patterns at various ontological periods becomes of key importance in formulating treatment plans for pediatric patients. Exposure to toxins or pharmaceutical agents or lack of medical treatment of a particular illness at sensitive periods of development could irreversibly disrupt the normal maturation of an individual. Observable consequences of such disruption may not appear until much later in life. For pharmacogenetics to deliver on its potential in pediatric patients, this complexity will need to be recognized and accommodated.[5] Furthermore, inconsistent replicability of clinical findings and various methodological limitations, including insufficient sample sizes, often compromise the applicability of published findings. Although large, prospective, multisite investigations are still needed, we illustrate selective clinical examples of the pharmacogenetics for treatment of transplantation, asthma, leukemia, and attention-deficit hyperactivity disorder (ADHD) in pediatric patients.

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