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

体外生命支持（ECLS）是危重患儿的一种挽救生命的技术。得到支助的儿童 ECLS接受许多药物来治疗危重疾病和基础疾病。不幸的是，大多数 在ECLS上为儿童开具的药物缺乏剂量信息。我们的初步数据表明， 在该人群中不同，因为ECLS回路组件（如过滤器和管路）以及生理 由危重疾病引发的改变对药物处置有很大影响。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 选择在ECLS儿童中安全有效地使用药物是不可行的， 药代动力学（PK）试验的结果有两个原因：1）ECLS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回路组合进行试验;因此需要大量的 儿童; 2）每当开发新的ECLS电路设备时， 量化新设备对剂量的影响。我们的团队已经证明了另一种方法的概念 通过使用复杂的基于生理学的药代动力学（PBPK）来解决这些限制 数学模型将实验室ECLS实验转化为床边给药建议。 然而，这种方法缺乏普遍性，因为它的应用目前仅限于两种药物 并且只有一种心肺ECLS模式（即，ECMO）。在本提案中，我们将以我们先前的工作为基础， 将该方法扩展到其他形式的ECLS（即，透析）用于儿童多种常用药物。 本提案的目的是评价通过连续性肾脏替代进行的ECLS回路药物提取 体外循环系统中的CRRT和体外膜氧合（ECMO）回路， 常用药物（AIM 1）。这些数据将用于开发ECLS-PBPK模型并预测给药， 接受CRRT和ECMO（AIM 2）支持的儿童。将对模型和给药建议进行验证 采用前瞻性PK研究（AIM 3）中收集的数据。在不同类型的ECLS中评价多种药物将 显示了这种方法的广泛普遍性。这些药物的普遍使用为公众提供了额外的 健康影响，并为拟议的研究提供可行性。

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.