Drug Delivery and Disposition, Department of Pharmaceutical and Pharmacological Sciences KU Leuven, Leuven, Belgium.
Comparative Perinatal Development, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium.
Expert Opin Drug Metab Toxicol. 2023 Jul-Dec;19(7):461-477. doi: 10.1080/17425255.2023.2237412. Epub 2023 Jul 28.
Perinatal asphyxia (PA) still causes significant morbidity and mortality. Therapeutic hypothermia (TH) is the only effective therapy for neonates with moderate to severe hypoxic-ischemic encephalopathy after PA. These neonates need additional pharmacotherapy, and both PA and TH may impact physiology and, consequently, pharmacokinetics (PK) and pharmacodynamics (PD).
This review provides an overview of the available knowledge in PubMed (until November 2022) on the pathophysiology of neonates with PA/TH. In vivo pig models for this setting enable distinguishing the effect of PA versus TH on PK and translating this effect to human neonates. Available asphyxia pig models and methodological considerations are described. A summary of human neonatal PK of supportive pharmacotherapy to improve neurodevelopmental outcomes is provided.
To support drug development for this population, knowledge from clinical observations (PK data, real-world data on physiology), preclinical (in vitro and in vivo (minipig)) data, and molecular and cellular biology insights can be integrated into a predictive physiologically-based PK (PBPK) framework, as illustrated by the I-PREDICT project (Innovative physiology-based pharmacokinetic model to predict drug exposure in neonates undergoing cooling therapy). Current knowledge, challenges, and expert opinion on the future directions of this research topic are provided.
围产期窒息（PA）仍然会导致显著的发病率和死亡率。在 PA 后出现中重度缺氧缺血性脑病的新生儿，只有治疗性低体温（TH）是唯一有效的治疗方法。这些新生儿需要额外的药物治疗，PA 和 TH 都可能影响生理机能，进而影响药代动力学（PK）和药效动力学（PD）。
本文综述了 2022 年 11 月前在 PubMed 上发表的有关 PA/TH 新生儿病理生理学的相关知识。在该环境下，体内猪模型可以区分 PA 和 TH 对 PK 的影响，并将这种影响转化为人类新生儿。描述了现有的窒息猪模型和方法学考虑因素。还提供了支持改善神经发育结局的药物治疗的人类新生儿 PK 的总结。
为了支持该人群的药物开发，可以将临床观察（PK 数据、生理方面的真实世界数据）、临床前（体外和体内（小型猪））数据以及分子和细胞生物学方面的知识整合到一个预测性生理 PK（PBPK）框架中，如 I-PREDICT 项目（创新的基于生理学的 PK 模型，用于预测接受冷却治疗的新生儿的药物暴露）所示。本文提供了当前关于该研究主题的知识、挑战和未来方向的专家意见。
