Investigation of Drug-Drug and Drug-Circuit Interactions in Children on Continuous Renal Replacement Therapy

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PROJECT SUMMARY/ABSTRACT Continuous renal replacement therapy (CRRT), a form of dialysis, is life saving for children with acute kidney injury. Despite this, children supported with CRRT are at still at high risk for death, with mortality rates exceeding 40%. This high mortality is thought to result in part from altered drug exposure. Altered drug exposure occurs from 1) drug-drug interactions due to the administration of multiple drugs; 2) multi-organ dysfunction; and 3) direct drug interaction and/or removal of drug by the CRRT circuit. As a result, for most drugs, optimal dosing in children on CRRT is unknown. The goal of this study is to determine optimal dosing of 5 commonly used drugs in children on CRRT. In AIM 1 we will determine how drugs interact with the CRRT machines by injecting five drugs singly and together into isolated, closed-loop CRRT circuits. In AIM 2 we will build physiologically based pharmacokinetic (PBPK) models to predict optimal drug dosing in children. PBPK models are computational models in which the body is represented as a set of virtual organ compartments linked by blood flow. Mathematical equations characterize changes in drug concentrations as the drug passes through the virtual organs. These mechanistic models can account for the impact of physiologic covariates such as age and disease and incorporate the impact of drug- drug interactions. Importantly, we can use the data from AIM 1 to build a CRRT “organ” in the PBPK model to account for the impact of CRRT on drug dosing. Finally in AIM 3 we will collect prospective drug concentration data from children who are on CRRT and one or more of the selected drugs. We will compare the observed concentration data from these children with the PBPK model-predicted concentration data in order to refine and validate the PBPK model. We will use the final PBPK model to predict optimal dosing under different scenarios such as drug co-administration and different CRRT settings. This study will determine the PK of common medications and interactions between drugs co-administered in children on CRRT. Results can be directly translated to the bedside and improve safety and effectiveness of drugs used in critically ill children on CRRT. Training will take place at the University of Utah under the mentorship of a leading expert in PBPK modeling. Through my training plan, I will develop the necessary skills for a career as an independent research scientist including the necessary technical skillset, completing coursework in pharmacology/pharmacokinetics, and the effective communication of data and results.