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: 10044662
• 负责人: Kevin M Watt
• 金额: $ 50.45万
• 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/10044662
• 关键词: Physiologically; Based; Pharmacokinetic; Approach; Determine

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）是危重儿童的一种挽救生命的技术。受资助的儿童 ECLS 接收大量药物来治疗危重疾病和基础疾病。不幸的是，大多数 ECLS 上给儿童开的药物缺乏剂量信息。我们的初步数据表明，剂量是 在此人群中有所不同，因为 ECLS 电路组件（如过滤器和管道）以及生理学 危重疾病引发的变化极大地影响药物处置。缺乏适当的剂量 信息是一项紧迫的、未得到满足的公共卫生需求，可能导致治疗失败和死亡。剂量 传统的 ECLS 方法无法实现儿童安全有效用药的选择 药代动力学 (PK) 试验有两个原因：1) ECLS 对药物处置的影响具有药物和年龄特异性， 需要对所有可能的药物、年龄和 ECLS 回路组合进行试验；从而需要大量的 孩子们; 2) 每当开发出新的 ECLS 电路设备时，就需要重复这些试验 量化新设备对剂量的影响。我们的团队已经证明了替代方法的概念 通过使用复杂的基于生理学的药代动力学 (PBPK) 解决这些限制 将实验室 ECLS 实验转化为床边剂量建议的数学模型。 然而，这种方法迄今为止缺乏普遍性，因为它的应用目前仅限于两种药物 且只有一种心肺 ECLS 模式（即 ECMO）。在本提案中，我们将在之前的工作基础上 将方法扩展到其他形式的 ECLS（即透析），用于儿童多种常用药物。 该提案的目的是评估通过连续肾脏替代进行药物的 ECLS 回路提取 离体系统中的治疗 (CRRT) 和体外膜氧合 (ECMO) 回路 10 常用药物（AIM 1）。这些数据将用于开发 ECLS-PBPK 模型并预测剂量 接受 CRRT 和 ECMO 支持的儿童 (AIM 2)。模型和剂量建议将得到验证 前瞻性 PK 研究 (AIM 3) 中收集的数据。在不同类型的 ECLS 中评估多种药物将 表明该方法具有广泛的普适性。这些药物的共同使用为公众提供了额外的 健康影响并为拟议研究提供可行性。