The overall goal of the Center for Genomic-and Ontogeny-Linked Dose Individualization and cLinical Optimization for Kids is to increase the body of knowledge related to variability in drug response in children. The pediatric clinical pharmacology expertise of the Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics at Children's Mercy Hospital is augmented by collaborations with partners at the University of Manchester, Duke University and the University of Kansas Medical Center with specialized expertise in quantitative systems pharmacology, metabolomics and statistical genomics. Using atomoxetine, a drug used to treat Attention-Deficit/Hyperactivity Disorder (ADHD) as proof-of principle of the overall concept, Project 1(Clinical) will utilize a response->exposure->dose paradigm and an exposure escalation dosing strategy to investigate ontogeny and genetic variation as sources of variability in drug response at the level of the target of drug action, the norepinephrine reuptake pump (NET/5LC6A2). In all projects - Project (Clinical), Project 2 (Translational) and the Pilot Project ? -omic technologies, such as next-generation sequencing and metabolomics, as well as quantitative systems pharmacology approaches will be applied to better characterize genetic and developmental sources of variability in drug response. The Pilot Project represents an exploratory analysis of an existing transcriptome and metabolomic dataset generated from 96 pediatric liver samples ranging in age from birth to 18 years. We propose to make this resource available to bioinformatic teams at other Specialized Centers to pursue research questions of mutual interest. Finally, the Specialized Center at Children's Mercy Hospital is committed to creating a rich environment for the education and training of the next generation of clinical and translational scientists dedicated to finding the drug and dose that is just right for their patients.
Knowledge of the influence of genetic variation and physiological changes that occur during growth and development on genes responsible for drug response in children is limited. Through the ?GOLDILOKs: Genomic- and Ontogeny-Linked Dose Individualization and cLinical Optimization for Kids? Specialized Center in Research in Pediatric Developmental Pharmacology, we propose to use information that makes each child unique ? their genome and stage of development ? to find the drug and dose that is ?just right? for them. To achieve this goal we will develop tools to allow drug doses to be individualized to achieve a desired amount of drug in the body, referred to as the ?exposure?. Achieving the same exposure in study participants allows us to investigate the effect of genetics and stage of development on the target of drug action, using a drug used to treat Attention-Deficit/Hyperactivity Disorder (ADHD), atomoxetine, as proof-of-principle for the concept. Through collaborations with partners at the University of Manchester, Duke University and the University of Kansas Medical Center with expertise in quantitative systems pharmacology, metabolomics and statistical genomics, the GOLDILOKs center introduces several innovations in pediatric developmental pharmacology, including 1) metabolomic analyses to discover ?metabotypes? predictive of response to atomoxetine, 2) measurement of pupil size as a biomarker of drug interaction with its target in the brain, 3) next generation sequencing technology to improve the quality of genetic information for CYP2D6, the primary pathway responsible for atomoxetine elimination, and 4) characterizing developmental changes in critical elements of the mathematical models used to determine drug doses. The GOLDILOKs Specialized Center is committed to creating an environment for training pediatricians, pharmacists and nurses to learn to think differently about clinical problems related to variability to drug response in children of all ages, and to become engaged in research to address these challenges.
