Genomic- and Ontogeny-Linked Dose Individualization and cLinical Optimization for Kids

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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.