Pediatric Pharmacology and Pharmacometrics Research Center, University Children's Hospital Basel (UKBB), Basel 4056, Switzerland.
Intensive Care and Department of Pediatric Surgery, Erasmus MC-Sophia Children's Hospital, Rotterdam, Netherlands.
Curr Pharm Des. 2019;25(5):483-495. doi: 10.2174/1381612825666190320135137.
In clinical pharmacokinetic (PK) studies, pregnant women are significantly underrepresented because of ethical and legal reasons which lead to a paucity of information on potential PK changes in this population. As a consequence, pharmacometric tools became instrumental to explore and quantify the impact of PK changes during pregnancy.
We explore and discuss the typical characteristics of population PK and physiologically based pharmacokinetic (PBPK) models with a specific focus on pregnancy and postpartum.
Population PK models enable the analysis of dense, sparse or unbalanced data to explore covariates in order to (partly) explain inter-individual variability (including pregnancy) and to individualize dosing. For population PK models, we subsequently used an illustrative approach with ketorolac data to highlight the relevance of enantiomer specific modeling for racemic drugs during pregnancy, while data on antibiotic prophylaxis (cefazolin) during surgery illustrate the specific characteristics of the fetal compartments in the presence of timeconcentration profiles. For PBPK models, an overview on the current status of reports and papers during pregnancy is followed by a PBPK cefuroxime model to illustrate the added benefit of PBPK in evaluating dosing regimens in pregnant women.
Pharmacometric tools became very instrumental to improve perinatal pharmacology. However, to reach their full potential, multidisciplinary collaboration and structured efforts are needed to generate more information from already available datasets, to share data and models, and to stimulate cross talk between clinicians and pharmacometricians to generate specific observations (pathophysiology during pregnancy, breastfeeding) needed to further develop the field.
由于伦理和法律原因，在临床药代动力学（PK）研究中，孕妇的代表性严重不足，这导致了该人群中潜在 PK 变化信息的缺乏。因此，药物计量学工具成为探索和量化妊娠期间 PK 变化影响的重要手段。
我们探讨和讨论了群体 PK 和基于生理的药代动力学（PBPK）模型的典型特征，特别关注妊娠和产后。
群体 PK 模型能够分析密集、稀疏或不平衡的数据，以探索协变量，以便（部分）解释个体间变异性（包括妊娠）并实现个体化给药。对于群体 PK 模型，我们随后使用酮咯酸数据的说明性方法来强调在妊娠期间对立体异构体特异性建模对于外消旋药物的相关性，而关于手术期间抗生素预防（头孢唑林）的数据则说明了在存在时间-浓度曲线的情况下胎儿隔室的特定特征。对于 PBPK 模型，我们首先概述了当前关于妊娠期间报告和论文的现状，然后介绍了一个头孢呋辛的 PBPK 模型，以说明在评估孕妇给药方案时 PBPK 的附加优势。
药物计量学工具在改善围产期药理学方面变得非常重要。然而，要充分发挥其潜力，需要多学科合作和有组织的努力，从现有数据集生成更多信息，共享数据和模型，并促进临床医生和药物计量学家之间的对话，以产生进一步发展该领域所需的特定观察结果（妊娠期间的病理生理学、母乳喂养）。
