Physiologically Based Pharmacokinetic Modelling in Critically Ill Children Receiving Anakinra While on Extracorporeal Life Support.

IF 4.6 2区医学 Q1 PHARMACOLOGY & PHARMACY Clinical Pharmacokinetics Pub Date : 2024-09-01 Epub Date: 2024-09-27 DOI:10.1007/s40262-024-01424-w

Samuel Dubinsky, Abdullah Hamadeh, Carina Imburgia, Autumn McKnite, J Porter Hunt, Kristy Wong, Cassandra Rice, Joseph Rower, Kevin Watt, Andrea Edginton

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Abstract

Background and objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

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重症儿童在接受体外生命支持治疗的同时接受 Anakinra 治疗的生理学药代动力学模型。

背景和目的：由于危重病和使用体外生命支持（ECLS）（如持续肾脏替代疗法（CRRT）和体外膜肺氧合（ECMO））相关的病理生理变化，药物的药代动力学通常会发生改变。本研究的目的是建立一个基于生理学的阿纳金拉（anakinra）儿童药代动力学（PBPK）模型，该模型考虑了与危重症和 ECLS 技术相关的生理变化，以指导适当的药物治疗：方法：首先在健康人中建立了阿纳金拉的 PBPK 模型，然后再推断用于接受 ECLS 的重症儿童。为了考虑透析回路对 Anakinra 清除率的影响，在儿科 PBPK 模型中加入了 CRRT 区间，并使用之前发表的一项体外研究数据进行参数化。此外，还在全身结构中加入了 ECMO 区室，以创建最终的 anakinra ECLS-PBPK 模型。通过比较预测浓度和观察到的患者数据，验证了最终的模型结构。由于指导该人群服用阿纳金拉的信息有限，因此进行了体内剂量模拟，以提供基线建议：结果：通过考虑生理变化和 ECLS 区间的增加，最终的 ECLS-PBPK 模型预测出了在接受皮下注射 anakinra 的青少年中观察到的血浆浓度。此外，剂量模拟表明，接受ECLS治疗的青少年体内的阿纳金拉暴露量与健康青少年相似：本研究开发的 Anakinra ECLS-PBPK 模型首次预测了同时接受 CRRT 和 ECMO 患者的血浆浓度。所提供的剂量模拟可为重症儿童使用 Anakinra 提供参考，并为未来的临床试验规划提供指导。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Clinical Pharmacokinetics 医学-药学

CiteScore

8.80

自引率

4.40%

发文量

审稿时长

6-12 weeks

期刊介绍： Clinical Pharmacokinetics promotes the continuing development of clinical pharmacokinetics and pharmacodynamics for the improvement of drug therapy, and for furthering postgraduate education in clinical pharmacology and therapeutics. Pharmacokinetics, the study of drug disposition in the body, is an integral part of drug development and rational use. Knowledge and application of pharmacokinetic principles leads to accelerated drug development, cost effective drug use and a reduced frequency of adverse effects and drug interactions.