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.

体外生活支持（ECLS）是危及生病的孩子的一种挽救生命的技术。孩子们得到了支持 ECL会收到许多药物来治疗危重疾病和潜在疾病。不幸的是，大多数 向儿童开出ECLS的药物缺乏给药信息。我们的初步数据表明，给药是 在该人群中有所不同，因为ECLS电路组件（例如过滤器和管道）以及生理学 危害疾病触发的改变显着影响药物处置。缺乏适当的给药 信息是一种紧急，未满足的公共卫生需求，可能导致治疗衰竭和死亡。剂量 在ECLS上选择安全有效地使用毒品以实现安全有效的毒品是不可行的 药代动力学（PK）试验的两个原因：1）ECL对药物处置的影响是药物和年龄特异性的， 需要对所有可能的药物，年龄和ECLS电路组合进行试验；因此需要大量 孩子们; 2）每当开发新的ECLS电路设备到 量化新设备对剂量的影响。我们的团队有替代方法的概念证明 通过使用基于生理的药代动力学（PBPK）来解决这些限制 数学模型将基准ECLS实验转化为床边剂量建议。 但是，到目前为止，这种方法缺乏可推广性，因为它的应用目前仅限于两种药物 只有一种心肺ECLS（即ECMO）。在此提案中，我们将在先前的工作基础上建立 将方法扩展到其他形式的ECL（即透析）中，用于儿童多种常用药物。 该提案的目的是通过连续肾脏置换来评估ECLS电路提取药物 在体内系统中，治疗（CRRT）和体外膜氧合（ECMO）电路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 CRRT和ECMO支持的孩子（AIM 2）。模型和剂量建议将得到验证 在前瞻性PK研究中收集的数据（AIM 3）。评估不同类型的ECL中的多种药物将 显示这种方法的广泛概括性。这些药物的共同用途提供了额外的公众 健康影响并赋予了拟议研究的可行性。