Smits Anne, Annaert Pieter, Van Cruchten Steven, Allegaert Karel
Neonatal Intensive Care Unit, University Hospitals Leuven, Leuven, Belgium.
Department of Development and Regeneration, KU Leuven, Leuven, Belgium.
Front Pharmacol. 2020 May 13;11:587. doi: 10.3389/fphar.2020.00587. eCollection 2020.
Therapeutic hypothermia (TH) is standard treatment for neonates (≥36 weeks) with perinatal asphyxia (PA) and hypoxic-ischemic encephalopathy. TH reduces mortality and neurodevelopmental disability due to reduced metabolic rate and decreased neuronal apoptosis. Since both hypothermia and PA influence physiology, they are expected to alter pharmacokinetics (PK). Tools for personalized dosing in this setting are lacking. A neonatal hypothermia physiology-based PK (PBPK) framework would enable precision dosing in the clinic. In this literature review, the stepwise approach, benefits and challenges to develop such a PBPK framework are covered. It hereby contributes to explore the impact of non-maturational PK covariates. First, the current evidence as well as knowledge gaps on the impact of PA and TH on drug absorption, distribution, metabolism and excretion in neonates is summarized. While reduced renal drug elimination is well-documented in neonates with PA undergoing hypothermia, knowledge of the impact on drug metabolism is limited. Second, a multidisciplinary approach to develop a neonatal hypothermia PBPK framework is presented. Insights on the effect of hypothermia on hepatic drug elimination can partly be generated from (human/animal) profiling of hepatic drug metabolizing enzymes and transporters. Also, endogenous biomarkers may be evaluated as surrogate for metabolic activity. To distinguish the impact of PA hypothermia on drug metabolism, neonatal animal data are needed. The conventional pig is a well-established model for PA and the neonatal Göttingen minipig should be further explored for PA under hypothermia conditions, as it is the most commonly used pig strain in nonclinical drug development. Finally, a strategy is proposed for establishing and fine-tuning compound-specific PBPK models for this application. Besides improvement of clinical exposure predictions of drugs used during hypothermia, the developed PBPK models can be applied in drug development. Add-on pharmacotherapies to further improve outcome in neonates undergoing hypothermia are under investigation, all in need for dosing guidance. Furthermore, the hypothermia PBPK framework can be used to develop temperature-driven PBPK models for other populations or indications. The applicability of the proposed workflow and the challenges in the development of the PBPK framework are illustrated for midazolam as model drug.
治疗性低温（TH）是围产期窒息（PA）和缺氧缺血性脑病的新生儿（≥36周）的标准治疗方法。TH通过降低代谢率和减少神经元凋亡来降低死亡率和神经发育残疾。由于低温和PA都会影响生理功能，因此预计它们会改变药代动力学（PK）。在这种情况下缺乏个性化给药的工具。基于新生儿低温生理学的PK（PBPK）框架将能够在临床上实现精准给药。在这篇文献综述中，涵盖了开发这种PBPK框架的逐步方法、益处和挑战。它有助于探索非成熟PK协变量的影响。首先，总结了关于PA和TH对新生儿药物吸收、分布、代谢和排泄影响的当前证据以及知识空白。虽然在接受低温治疗的PA新生儿中，肾脏药物清除率降低已有充分记录，但对药物代谢影响的了解有限。其次，提出了一种开发新生儿低温PBPK框架的多学科方法。关于低温对肝脏药物清除影响的见解部分可以从肝脏药物代谢酶和转运体的（人类/动物）分析中获得。此外，内源性生物标志物可作为代谢活性的替代物进行评估。为了区分PA和低温对药物代谢的影响，需要新生儿动物数据。传统猪是PA的成熟模型，而新生儿哥廷根小型猪应在低温条件下进一步探索用于PA，因为它是非临床药物开发中最常用的猪品系。最后，提出了一种为该应用建立和微调化合物特异性PBPK模型的策略。除了改善低温期间使用药物的临床暴露预测外，开发的PBPK模型还可应用于药物开发。正在研究用于进一步改善接受低温治疗新生儿结局的附加药物治疗，所有这些都需要给药指导。此外，低温PBPK框架可用于为其他人群或适应症开发温度驱动的PBPK模型。以咪达唑仑作为模型药物说明了所提出工作流程的适用性以及PBPK框架开发中的挑战。
