Pediatric Pharmacogenomics

Abstract

Synopsis The dose-exposure-response relationship for drugs may differ in pediatric patients compared to adults due to developmental changes in processes involved in drug disposition (absorption, distribution, metabolism and excretion) and drug response. This relative knowledge deficit has complicated drug efficacy and safety labeling of drugs for pediatric use. With the legislative changes that have occurred in the US and Europe over the last 20 years, many clinical studies have been conducted to establish drug dose-exposure relationships across the pediatric age spectrum from birth to adolescence. However, genetic variation has seldom been included in these investigations. This article applies a systematic approach to determine the relative contribution of development and genetic variation on drug disposition and response using HMG-CoA reductase inhibitors as a model. Application of the approach drives the collection of information relevant to understanding the potential contribution of ontogeny and genetic variation to statin dose-exposure-response in children, and identifies important knowledge deficits to be addressed through the design of future studies.

Pediatric Beta Blocker Therapy: A Comprehensive Review of Development and Genetic Variation to Guide Precision-Based Therapy in Children, Adolescents, and Young Adults

“…Therefore, the intention of the remainder of this review is to present three essential points that must be considered when acquiring knowledge related to variability in beta blocker disposition and response in the developing cardiac patient. This approach has been previously utilized to detect knowledge deficits linked to the contribution of ontogeny and genetic variation on drug disposition and response in children [ 37 , 38 ].…”

Correlates of Myopathy in Diabetic Patients Taking Statins

“…Statin-associated adverse reactions display significant variability among patients due to different age groups, genetics, body habitus, alcohol use, concomitant drug use, and comorbid conditions [ 21 ]. Patients more significantly affected by statin use include [ 21 ]: (i) Older people with lower lean muscular mass, multiple drug use, and lessened metabolic function [ 21 , 25 ], (ii) HIV (human immunodeficiency virus) patients with increased drug interaction risk owing to coadministration of anti-viral agents (ritonavir, boceprevir, telaprevir) with statins especially simvastatin and lovastatin [ 21 , 26 ], (iii) People with East Asian ancestry who have higher serum levels of statins such as rosuvastatin than Caucasians [ 21 , 27 ], (iv) Pediatric age group whose dose-exposure-response relationships are poorly defined [ 21 , 28 ], (v) Familial hypercholesterolemia (FH) patients who are drug dependent and are usually on a combination of three to four drugs [ 21 , 29 ], and (vi) chronic kidney disease (CKD) patients who have the impaired capacity to excrete statin [ 21 , 30 ]. Therefore, these diverse patient populations require variable statin types having different pharmacokinetic mechanisms and dosages, or statins are contraindicated [ 21 ].…”

Pharmacogenetics in Clinical Pediatrics: Challenges and Strategies

“…Along with physical growth and cognitive development, the expression patterns of genes in drug response pathways evolve and change over time [7,8]. Sentinel studies have emphasized the developmental ontogeny of pharmacogenetic pathways, which include drug metabolism enzymes, drug transporters and drug targets [9–12].…”