Personalized Therapeutics through Pharmacokinetics and Pharmacogenomics
Our research seeks to identify pharmacokinetic (PK), pharmacodynamic (PD) and pharmacogenetic (PGx) factors to explain differences in clinical response to drugs and adverse events in pediatric patients. One important focus area is immunomodulating therapies in transplantation and rheumatology. For decades clinicians have struggled with individualized dosing of drugs to improve clinical outcomes and reduce toxic side effects. With funding from a Place Outcome Award by The James M. Anderson Center for Health Systems Excellence, we worked with David Hooper, MD, and members of Nephrology, Biomedical Informatics, and the Adherence Center and developed a web-based therapeutic decision support system (dashboard) with a graphical user interface. The dashboard is linked to the electronic health record and provides real-time views of individual patient data that are essential for the management of therapy and will alert providers of increased risk of toxicity and drug interaction potential. The novel dashboard includes pharmacokinetic summaries of all immunosuppressive drugs and real-time adherence data and is made available to providers to enhance their medication management decision making. We also continue to participate in the Genetic Pharmacology Service, the first of its kind in a pediatric institution, expanding our pharmacogenetics panels and services for neuropsychiatric drugs, codeine and warfarin.
Pharmacometrics and Systems Pharmacology
As part of the personalized pain initiative, we work with Anesthesia on novel pharmacological approaches that use the patient’s drug metabolizing genotype and phenotype to manage pain with morphine and related drugs, reduce adverse events and avoid clinically significant drug/drug interactions. A successful joint effort includes a study on the disposition of morphine and metabolites that identified important PGx factors in postsurgical patients that could help predict morphine’s dose. This finding and its potential role in personalizing analgesia is currently being investigated in a larger cohort of patients. A joint effort with the Center for Bariatric Research and Innovation funded through the translational research initiative was the successful completion of a PK study of propofol in obese patients undergoing bariatric surgery and the development of an evidence based dosing algorithm. With the Cancer and Blood Diseases Institute, we completed a PK-guided study of sirolimus in children with NF1 and plexiform neurofibromas. published. As part of the project we have initiated an in-vitro/in-vivo correlation program studying the genetics and developmental aspects of sirolimus disposition. We have identified important differences in metabolic pathways in young patients, a finding that directly benefits the individualized dosing of patients with complicated vascular anomalies who participate in a sirolimus safety and efficacy study funded by the FDA.
T32 Program in Pediatric Clinical Pharmacology
We are one of three sites awarded a pediatric clinical and developmental pharmacology training grant (T32) from the National Institute of Health. This postdoctoral program trains the next generation of clinical investigators to assume leadership roles in developing innovative approaches that will enhance pediatric therapeutics. Many medicines have not been scientifically evaluated for use in children and are either used unlicensed or in an off-label manner. In addition, far fewer medicines have been developed specifically to treat childhood diseases. One of our major goals is to provide research support and training that enhances the knowledge of our fellows related to the application of pharmacokinetics and pharmacogenetics/genomics to individualized therapy. Current fellows were selected from a pool of high quality pediatric subspecialty trainee candidates: Dawn Pinchasik, MD, is a third year fellow in Pediatric Hematology-Oncology and our first 2013 graduate. Jason Wiles, MD, is a Neonatology fellow, and Andrea Hahn, MD and Kevin Downes, MD, are Infectious Diseases fellows.