Physiologically-Based Pharmacokinetic Approach to Determine Dosing on Extracorporeal Life Support

基于生理学的药代动力学方法来确定体外生命支持的剂量

• 批准号: 10116989
• 负责人: Kevin M Watt
• 金额: $ 59.35万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-10-21 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116989
• 关键词: Address; Affect; Age; Binding Proteins; Birth; Cardiopulmonary; Cessation of life; Child; Child Support; Childhood; Clinical; Clinical Research; Clinical Trials; Collection; Critical Illness; Critically ill children; Data; Dialysis procedure; Disease; Doctor of Philosophy; Dose; Drug Kinetics; Drug Prescriptions; Drug usage; Effectiveness; Enrollment; Environment; Equipment; Extracorporeal Membrane Oxygenation; Failure; Goals; Infrastructure; Investigational New Drug Application; Knowledge; Label; Laboratories; Life; Mathematics; Medical Device; Modeling; Monitoring Clinical Trials; National Institute of Child Health and Human Development; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Population; Principal Investigator; Protocols documentation; Public Health; Recommendation; Recording of previous events; Renal Replacement Therapy; Research; Research Institute; Research Personnel; Safety; Sampling; Savings; Science; Special Population; System; Technology; Therapeutic; Training; Translating; Translational Research; Validation; Work; appropriate dose; base; data management; dose information; drug action; drug disposition; experience; experimental study; human old age (65+); improved; in vivo; individualized medicine; lipophilicity; mathematical model; pediatric drug development; pharmacokinetic model; prospective; response; skills; tool

Extracorporeal life support (ECLS) is a life-saving technology in critically ill children. Children supported with ECLS receive numerous drugs to treat critical illness and the underlying disease. Unfortunately, the majority of drugs prescribed to children on ECLS lack dosing information. Our preliminary data demonstrate that dosing is different in this population because the ECLS circuit components, like filters and tubing, as well as physiologic alterations triggered by critical illness affect drug disposition substantially. The lack of appropriate dosing information is an urgent, unmet public health need that can result in therapeutic failure and death. Dose selection to achieve safe and effective use of drugs in children on ECLS is not feasible with traditional pharmacokinetic (PK) trials for two reasons: 1) the effect of ECLS on drug disposition is drug- and age-specific, necessitating trials for all possible drug-, age-, and ECLS circuit combinations; thus requiring large numbers of children; and 2) these trials would need to be repeated whenever new ECLS circuit equipment is developed to quantify the effect of the new equipment on dosing. Our team has proof of concept of an alternative approach that addresses these limitations by using sophisticated physiologically-based pharmacokinetic (PBPK) mathematical models to translate benchside ECLS experiments into bedside dosing recommendations. However, this approach lacks generalizability thus far because its application is currently limited to two drugs and only one mode of cardio-pulmonary ECLS (i.e., ECMO). In this proposal, we will build upon our prior work to expand the approach to other forms of ECLS (i.e., dialysis) for multiple commonly used drugs in children. The objective of this proposal is to evaluate ECLS circuit extraction of drugs by continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO) circuits in an ex vivo system for 10 commonly used drugs (AIM 1). These data will be used to develop ECLS-PBPK models and predict dosing in children supported with CRRT and ECMO (AIM 2). The models and dosing recommendations will be validated with data collected in a prospective PK study (AIM 3). Evaluating multiple drugs in different types of ECLS will show the broad generalizability of this approach. The common use of these drugs provides additional public health impact and lends feasibility to the proposed research.

体外生命支持（ECLS）是一项挽救危重儿童生命的技术。受资助的儿童