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

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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.