Project Details

E.W. "Al" Thrasher

Status: Funded - Open

Effects of Pediatric Liver Adiposity on Statin Disposition and Response

Jonathan Wagner, DO, FAAP

Summary

BACKGROUND: We have previously observed unusually high plasma statin concentrations in obese children, independent of genetics, suggesting that obesity-related factors may contribute to diminished liver drug uptake and higher peripheral tissue exposure (e.g. brain, muscles) in children. A situation which can lead to adverse drug reaction (e.g. muscle pain, neurodevelopmental delay) and inadequate response to the drug. Thus, it is pivotal to understand the physiologic factors that contribute to the observed altered drug disposition and response for obese children to inform the CV care of these patients. GAP: There remains a critical information gap in how liver fat affects liver cell processes, such as liver drug transport (e.g. drug disposition) and cholesterol regulation in the liver (e.g. drug response). HYPOTHESIS: 1) Increasing liver adiposity, measured by magnetic resonance imaging (MRI) quantification, contributes to diminished liver uptake of statins placing obese children at higher risk for toxicity. 2) Increasing liver adiposity, measured by MRI quantification, contributes to less mevalonate (a marker of drug response) reduction placing obese children administered a statin at higher risk for treatment failure. METHODS: Single center investigation in obese and non-obese children and adolescents 8-21 years of age (n=50) that are dosed rosuvastatin. Only those with normal, wild-type SLCO1B1 c.521TT genotype and those that have never been dosed a statin will be included in the study. RESULTS: Pending IMPACT: The work proposed will improve our understanding of the role that liver adiposity has on hepatic drug transport and response serving as a guide to refine not only current statin dosing strategies, but also dosing for other drugs utilized in obese children with comparable drug disposition pathways (e.g. anti-diabetic agents, angiotensin receptor blockers). The rationale for this project is that establishing a relationship between liver adiposity, hepatic transporter function, and cholesterol biosynthesis will allow us to develop computerized decision-support tools to assist clinicians with statin utilization and optimal dose selection for children with obesity who are suitable candidates for pharmacotherapy. Website Link: https://researchers.childrensmercy.org/display/336849