Pharmacologic Basis of Pediatric Therapeutics
Center Leader: Jeffrey Barrett, PhD
Pharmacotherapy is generally concerned with the safe and effective management of drug administration. It implies an understanding of drug pharmacokinetics and pharmacodynamics – how the body uses the drugs and the physiologic effects of medications – to optimize a patient’s response to treatment through effective dosing.
Pediatric pharmacotherapy presents several challenges: developmental changes in children may alter drug kinetics, pathophysiologic differences may alter pharmacodynamics, and the cause of a disease in a child may be different from that in an adult. Other factors may also result in great variation in safety and efficacy outcomes. The situation becomes more complex for critically ill children and neonates given the paucity of well-controlled pediatric clinical trials.
Four axioms define the current state of pediatric therapeutics: limited opportunities exist to study pediatric populations; funds for such endeavors are sparse; some assumptions regarding adult pharmacotherapy are portable to pediatric populations while others are not; and the diversity of various pediatric subgroups based on age, indication, disease or illness makes generalizing across such groups problematic and potentially dangerous.
The emphasis of the Pharmacologic Basis of Pediatric Therapeutics Research Affinity Group centers on the premise that more informative clinical trials are needed in targeted populations for which the medical need is greatest. Such investigations are more productive when therapeutic area knowledge regarding clinical indications, drug actions, developmental status and other factors that may alter drug kinetics or dynamics are assembled into quantitative models that describe the intended clinical setting. The addition of research tools and techniques to improve the quality and information content of data collected from such investigations are also essential elements to study of pediatric pharmacology.
The affinity group’s efforts have therefore focused on assessing drug utilization within the inpatient hospital setting, and developing robust, analytical methods to support pharmacokinetic studies. As part of its effort, the affinity group also integrates modeling and simulation approaches to facilitate clinical trial simulation before protocols are finalized.
This recipe has been used for several collaborative investigations with anesthesia/critical care, neonatology, infectious disease and oncology with agents including dexmedetomidine, clonidine, fluconazole and actinomycin-D.
Moreover, the affinity group, with its heightened understanding of clinical trial modeling and simulation techniques, guides such investigations and provides mentorship opportunities for Children’s Hospital investigators seeking to learn such techniques. The group maintains close collaboration with the NIH-governed Pediatric Pharmacology Research Unit Network, which has reviewed and endorsed several investigations.
The Pharmacologic Basis of Pediatric Therapeutics Research Affinity Group’s other collaborations include pharmacometrics training and analysis with the Metrum Research Group, an informatics approach to pediatric pharmacotherapy with the Food and Drug Administration, and mechanisms for studying drug utilization with the National Institute of Child’s Health and Development.
In the coming year the affinity group will explore microdialysis, a technique to measure drug levels in tissues, and positron emission tomography scanning as research tools to further expand quantitative pharmacologic investigations. Members of the group are also exploring the use of discrete-event simulation (a probability-based modeling approach to simulate trial outcomes) as a technique to optimize patient enrollment and study-design strategies.
The affinity group participates in a bi-weekly ejournal club sponsored by the Metrum Research Group and will host a spring symposium highlighting new technologies.