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

> **NIH NIH F31** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2022 · $37,785

## Abstract

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.

## Key facts

- **NIH application ID:** 10466146
- **Project number:** 1F31DK130542-01A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Autumn Mcknite
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $37,785
- **Award type:** 1
- **Project period:** 2022-07-01 → 2026-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466146

## Citation

> US National Institutes of Health, RePORTER application 10466146, Investigation of Drug-Drug and Drug-Circuit Interactions in Children on Continuous Renal Replacement Therapy (1F31DK130542-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10466146. Licensed CC0.

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