School of Pharmacy, Faculty of Science, University of Waterloo, Waterloo, ON, Canada.
Department of Pediatrics, School of Medicine, University of Utah, Salt Lake City, UT, USA.
Clin Pharmacokinet. 2024 Sep;63(9):1343-1356. doi: 10.1007/s40262-024-01424-w. Epub 2024 Sep 27.
Because of the pathophysiological changes associated with critical illness and the use of extracorporeal life support (ECLS) such as continuous renal replacement therapy (CRRT) and extracorporeal membrane oxygenation (ECMO), the pharmacokinetics of drugs are often altered. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for anakinra in children that accounts for the physiological changes associated with critical illness and ECLS technology to guide appropriate pharmacotherapy.
A PBPK model for anakinra was first developed in healthy individuals prior to extrapolating to critically ill children receiving ECLS. To account for the impact of anakinra clearance by the dialysis circuit, a CRRT compartment was added to the pediatric PBPK model and parameterized using data from a previously published ex-vivo study. Additionally, an ECMO compartment was added to the whole-body structure to create the final anakinra ECLS-PBPK model. The final model structure was validated by comparing predicted concentrations with observed patient data. Due to limited information in guiding anakinra dosing in this population, in-silico dose simulations were conducted to provide baseline recommendations.
By accounting for changes in physiology and the addition of ECLS compartments, the final ECLS-PBPK model predicted the observed plasma concentrations in an adolescent receiving subcutaneous anakinra. Furthermore, dosing simulations suggest that anakinra exposure in adolescents receiving ECLS is similar to that in healthy counterparts.
The anakinra ECLS-PBPK model developed in this study is the first to predict plasma concentrations in a population receiving simultaneous CRRT and ECMO. Dosing simulations provided may be used to inform anakinra use in critically ill children and guide future clinical trial planning.
由于与危重病相关的病理生理变化以及体外生命支持（ECLS）的使用，如连续肾脏替代治疗（CRRT）和体外膜氧合（ECMO），药物的药代动力学常常发生改变。本研究的目的是建立一种能够解释与危重病和 ECLS 技术相关的生理变化的依那西普群体药代动力学（PBPK）模型，以指导合理的药物治疗。
首先在健康个体中建立依那西普的 PBPK 模型，然后外推至接受 ECLS 的危重病儿童。为了考虑依那西普被透析回路清除的影响，在儿科 PBPK 模型中添加了 CRRT 隔室，并使用先前发表的离体研究数据进行参数化。此外，在全身结构中添加了 ECMO 隔室，以创建最终的依那西普 ECLS-PBPK 模型。通过比较预测浓度与观察到的患者数据来验证最终模型结构。由于在该人群中指导依那西普给药的信息有限，因此进行了计算机模拟剂量研究，以提供基线建议。
通过考虑生理学变化和 ECLS 隔室的添加，最终的 ECLS-PBPK 模型预测了接受皮下依那西普治疗的青少年患者的观察到的血浆浓度。此外，剂量模拟表明，接受 ECLS 的青少年患者的依那西普暴露量与健康对照者相似。
本研究中建立的依那西普 ECLS-PBPK 模型是首个预测同时接受 CRRT 和 ECMO 治疗的人群中血浆浓度的模型。提供的剂量模拟可能用于指导危重病儿童中依那西普的使用，并指导未来的临床试验规划。
