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

• 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
• 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

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.

项目概要/摘要 连续替代疗法 (CRRT) 是一种肾脏透析形式，可挽救患有急性肾病的儿童的生命 尽管如此，接受 CRRT 治疗的儿童仍然面临很高的死亡风险，死亡率很高。 超过 40% 的高死亡率被认为部分是由于药物暴露的改变造成的。 暴露发生于 1) 由于服用多种药物而导致的药物间相互作用；2) 多器官； 3) 直接药物相互作用和/或通过 CRRT 回路去除药物 因此，对于大多数人来说。 ，儿童 CRRT 的最佳剂量尚不清楚。 本研究的目的是确定 AIM 1 儿童 CRRT 中 5 种常用药物的最佳剂量。 我们将通过将五种药物单独或一起注射到 CRRT 机器中来确定药物如何与 CRRT 机器相互作用。 在 AIM 2 中，我们将构建基于生理学的药代动力学 (PBPK)。 预测儿童最佳药物剂量的模型 PBPK 模型是身体处于其中的计算模型。 表示为一组由血流连接的虚拟器官隔室。 这些机械模型可以模拟药物通过虚拟器官时药物浓度的变化。 考虑年龄和疾病等生理协变量的影响，并纳入药物的影响 重要的是，我们可以使用 AIM 1 的数据在 PBPK 模型中构建 CRRT“器官” 最后，在 AIM 3 中，我们将收集预期药物浓度。 我们将比较观察到的 CRRT 和一种或多种选定药物的儿童的数据。 将这些儿童的浓度数据与 PBPK 模型预测的浓度数据相结合，以便精炼 并验证 PBPK 模型，我们将使用最终的 PBPK 模型来预测不同情况下的最佳剂量。 诸如药物联合给药和不同 CRRT 设置等场景。 这项研究将确定常见药物的 PK 以及联合用药之间的相互作用。 儿童接受 CRRT 的结果可以直接转化为床边并提高安全性和有效性。 用于重症儿童药物的 CRRT 培训将在犹他大学下进行。 PBPK 建模领域领先专家的指导 通过我的培训计划，我将培养必要的技能。 作为独立研究科学家的职业生涯，包括必要的技术技能，完成 药理学/药代动力学课程，以及数据和结果的有效沟通。

项目成果

Maximum likelihood estimation of renal transporter ontogeny profiles for pediatric PBPK modeling.

用于儿科 PBPK 建模的肾转运蛋白个体发育概况的最大似然估计。

• 发表时间: 2024-04
• 作者: Hunt, J Porter;Dubinsky, Samuel;McKnite, Autumn M;Cheung, Kit Wun Kathy;van Groen, Bianca D;Giacomini, Kathleen M;de Wildt, Saskia N;Edginton, Andrea N;Watt, Kevin M
• 通讯作者: Watt, Kevin M

Meropenem extraction by ex vivo extracorporeal life support circuits.

通过离体体外生命支持回路提取美罗培南。

• 发表时间: 2023-12
• 作者: Honeycutt, Christopher Cole;McDaniel, Charles Griffin;McKnite, Autumn;Hunt, J Porter;Whelan, Aviva;Green, Danielle J;Watt, Kevin M
• 通讯作者: Watt, Kevin M