Department of Pharmaceutical and Pharmacological Sciences.
Department of Development and Regeneration and Regeneration, KU Leuven, Leuven, Belgium.
Expert Opin Drug Metab Toxicol. 2022 May;18(5):301-312. doi: 10.1080/17425255.2022.2099836. Epub 2022 Jul 15.
There is a need for structured approaches to inform on pharmacotherapy in preterm neonates. With their proven track record up to regulatory acceptance, physiologically based pharmacokinetic (PBPK) modeling and simulation provide a structured approach, and hold the promise to support drug development in preterm neonates.
Compared to general and pediatric use of PBPK modeling, its use to inform pharmacotherapy in preterms is limited. Using a systematic search (PBPK + preterm), we retained 25 records (20 research papers, 2 letters, 3 abstracts). We subsequently collated the published information on PBPK software packages (PK-Sim®, Simcyp®), and their applications and optimization efforts in preterm neonates. It is encouraging that applications cover a broad range of scenarios (pharmacokinetic-dynamic analyses, drug-drug interactions, developmental pharmacogenetics, lactation related exposure) and compounds (small molecules, proteins). Furthermore, specific compartments (cerebrospinal fluid, tissue) or (patho)physiologic processes (cardiac output, biliary excretion, first pass metabolism) are considered.
Knowledge gaps exist, giving rise to various levels of uncertainty in PBPK applications in preterm neonates. To improve this, we need cross talk between clinicians and modelers to generate and integrate knowledge (PK datasets, system knowledge, maturational physiology and pathophysiology) to further refine PBPK models.
在早产儿中提供药物治疗信息需要采用结构化的方法。基于生理学的药代动力学（PBPK）建模和模拟已经通过了监管部门的验证，是一种结构化的方法，有望为早产儿的药物开发提供支持。
与 PBPK 在一般人群和儿科人群中的应用相比，其在早产儿中用于提供药物治疗信息的应用有限。通过系统搜索（PBPK + 早产儿），我们保留了 25 条记录（20 篇研究论文、2 封信件、3 篇摘要）。随后，我们整理了已发表的关于 PBPK 软件包（PK-Sim ® 、Simcyp ® ）及其在早产儿中的应用和优化工作的信息。令人鼓舞的是，这些应用涵盖了广泛的场景（药代动力学-动力学分析、药物-药物相互作用、发育药理学、与哺乳相关的暴露）和化合物（小分子、蛋白质）。此外，还考虑了特定的隔室（脑脊液、组织）或（病理）生理过程（心输出量、胆汁排泄、首过代谢）。
在早产儿中应用 PBPK 存在知识空白，导致存在各种程度的不确定性。为了改善这一点，我们需要临床医生和建模人员之间进行交流，以生成和整合知识（PK 数据集、系统知识、成熟的生理学和病理生理学），从而进一步完善 PBPK 模型。
