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

儿童连续肾脏替代治疗药物-药物和药物-回路相互作用的调查

基本信息

批准号：
10649452
负责人：
Autumn Mcknite
金额：
$ 3.87万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649452
关键词：
Acute Renal Failure with Renal Papillary Necrosis Adsorption Age Binding Proteins Biochemical Blood flow Calibration Child Child Support Childhood Clinical Clinical Pharmacology Clinical Research Combined Modality Therapy Complex Computer Models Critical Illness Critically ill children Data Development Plans Dialysis procedure Disease Dose Drug Exposure Drug Interactions Drug Kinetics Drug usage Effectiveness Equation Excision Functional disorder Goals Guidelines Individual Investigation Knowledge Life Link Mathematics Medical Mentorship Modeling Organ Patients Pharmaceutical Preparations Pharmacology Physiological Physiology Polypharmacy Population Process Public Health Qualifying Recommendation Renal Replacement Therapy Research Research Design Safety Sample Size Scientist Technical Expertise Testing Training Translating Translational Research Universities Utah appropriate dose career career development data communication drug action drug clearance drug disposition drug efficacy high risk improved in vivo lipophilicity medication safety model design mortality mortality risk pediatric drug development pediatric patients pharmacokinetic model physiologically based pharmacokinetics predictive modeling prospective response skill acquisition skills treatment optimization virtual

项目摘要

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.

项目摘要/摘要连续肾脏替代疗法（CRRT）是一种透析形式，是急性肾脏的生命受伤。尽管如此，获得CRRT支持的儿童仍处于死亡的高风险，死亡率超过40％。人们认为这种高死亡率部分是由于药物暴露的改变而导致的。药物改变暴露于1）由于多种药物的给药而导致的药物相互作用； 2）多器官功能障碍； 3）通过CRRT电路直接进行药物相互作用和/或去除药物。结果，大多数药物，在CRRT上儿童的最佳剂量是未知的。这项研究的目的是确定CRRT儿童中5种常用药物的最佳剂量。在目标1中我们将通过单独注入五种药物并共同注入五种药物来确定药物如何与CRRT机器相互作用孤立的闭环CRRT电路。在AIM 2中，我们将建立基于物理的药代动力学（PBPK）预测儿童最佳药物给药的模型。 PBPK模型是人体所在的计算模型表示为一组由血流连接的虚拟器室。数学方程式的特征当药物通过虚拟器官时，药物浓度的变化。这些机械模型可以解释生理协变量（例如年龄和疾病）的影响，并结合了药物的影响药物相互作用。重要的是，我们可以使用AIM 1的数据来在PBPK模型中构建CRRT“器官” 解释CRRT对药物剂量的影响。最后，在AIM 3中，我们将收集预期的药物浓度来自CRRT和一种或多种选定药物的儿童的数据。我们将比较观察到的这些儿童的浓度数据具有PBPK模型预测的浓度数据，以完善并验证PBPK模型。我们将使用最终的PBPK模型来预测不同的最佳剂量诸如药物共同给药和不同的CRRT设置之类的方案。这项研究将确定共同管理的普通药物的PK和相互作用 CRRT的孩子。结果可以直接转化为床边，并提高安全性和有效性在CRRT上使用的危重儿童的药物。培训将在犹他大学下进行 PBPK建模领先专家的遗产。通过我的培训计划，我将发展必要的技能作为独立研究科学家的职业，包括必要的技术技能，完成药理学/药代动力学的课程以及数据和结果的有效交流。