Considerations for Implementing Precision Therapeutics for Children

Abstract

Improving the utilization of pharmacologic agents in the pediatric population yields significant, perhaps life‐long, benefits. Genetic factors related to the disposition of a medication or an alteration at the target receptor site contributes to the observed variability of exposure and response between individuals. An additional source of this variability specific to the pediatric population is ontogeny, where age‐specific changes during development may require dose adjustments to obtain the same levels of drug exposure and response. With significant improvements in characterizing both the ontogeny and genetic contributions of drug metabolizing enzymes, the time is right to begin placing more emphasis on response rather than only the dose‐exposure relationship. The amount of drug target receptors and the relative affinity for binding at that target site may require different levels of systemic exposure to achieve a desired response. Concentration‐controlled studies can identify the needed exposure for a response at the drug target, the level of expression of the target site in an individual patient, and the tools required to individualize response. Although pediatrics represents a large spectrum of growth and development, developing tools to improve drug delivery for each individual patient across the spectrum of the ages treated by clinicians remains valuable.

Who Believes They Are “Just Average”: Informing the Treatment of Individual Patients Using Population Data

“…“Somewhere in the middle” would not be an uncommon response, and, in a recent commentary, my colleagues and I rather simplistically suggest that the optimum exposure may be a function of drug target expression, itself subject to influence by genetic variation. Extending this argument further we illustrate the challenges of translating drug target genotype information from “population” statistical association studies to actionable information for individual patients . Why is it that our traditional approaches to collect more and more data on a population basis (covariates for population pharmacokinetic models; genetic variants associated with drug response) have not translated into a readily demonstrative impact on the treatment of individual patients?…”

“…Extending this argument further we illustrate the challenges of translating drug target genotype information from "population" statistical association studies to actionable information for individual patients. 3 Why is it that our traditional approaches to collect more and more data on a population basis (covariates for population pharmacokinetic models; genetic variants associated with drug response) have not translated into a readily demonstrative impact on the treatment of individual patients?…”

<p>Pharmacogenomic Testing In Pediatrics: Navigating The Ethical, Social, And Legal Challenges</p>

“…In addition to PGx variations, there are several other factors that impact drug response in children, which can affect dosing and exposure levels 72–75. One of the primary challenges to the use and interpretation of PGx testing in children is the developmental changes in gene expression 76–80. Within the span of a few weeks to months after birth, the levels of drug absorption, transport, and metabolism alter significantly 81.…”

“…Much has been written regarding genetic testing in children in general 102–111. However, fewer papers have been published specifically about the appropriateness of PGx testing in children 76,112–114. Guidelines from professional organizations focus on the benefits of testing to the child103,115 and support the use of PGx testing, particularly when the clinical utility has been demonstrated in pediatric studies 102.…”

Safe and effective medication utilization in pediatric patients requiring rehabilitation services during the Coronavirus pandemic of 2019

“…Furthermore, large differences between prescribing practices, drug clearance and clinical responses exist between pediatric patients with cerebral palsy [16,17]. This highlights the need for our specialty to start treating individual patients as individuals by more precisely capturing factors associated with variations in the concentration of the medication in different compartments and, ultimately, in clinical responses [18].…”