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

体外生命支持(ECLS)是一种拯救危重儿童生命的技术。受支持的儿童 ECL接受许多治疗危重疾病和潜在疾病的药物。不幸的是，大多数人 在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 在这个群体中不同，因为ECLS电路组件，如过滤器和管子，以及生理 由危重疾病引发的变化在很大程度上影响药物处置。缺乏适当的剂量 信息是一种紧急的、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上实现儿童安全有效用药的传统方法是不可行的 药代动力学(PK)试验有两个原因：1)ECLS对药物处置的影响是药物和年龄特定的， 需要对所有可能的药物、年龄和ECLS电路组合进行试验；因此需要大量的 2)每当开发新的ECLS电路设备时，这些试验将需要重复 量化新设备对配药的影响。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的药代动力学(PBPK)来解决这些限制 将台式ECLS实验转化为床边给药建议的数学模型。 然而，这种方法到目前为止缺乏普适性，因为它的应用目前仅限于两种药物 心肺循环ECL只有一种模式(即ECMO)。在这份提案中，我们将在先前工作的基础上再接再厉 将方法扩展到儿童多种常用药物的其他形式的ECLS(即透析)。 这项建议的目的是评价连续性肾脏置换对药物的ECLS循环提取。 体外治疗(CRRT)和体外膜氧合(ECMO)电路 常用药物(AIM 1)。这些数据将用于开发ECLS-PBPK模型和预测 接受CRRT和ECMO支持的儿童(目标2)。模型和剂量建议将得到验证 使用前瞻性PK研究中收集的数据(AIM 3)。在不同类型的ECL中评估多种药物将 展示了这种方法的广泛普适性。这些药物的普遍使用为公众提供了额外的 对健康的影响，并为拟议的研究提供了可行性。

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.