Simcyp Limited, Blades Enterprise Centre, John Street, Sheffield S2 4SU.
Curr Drug Metab. 2012 Jul;13(6):695-720. doi: 10.2174/138920012800840374.
The physiological changes that occur in the maternal body and the placental-foetal unit during pregnancy influence the absorption, distribution, metabolism, and excretion (ADME) of xenobiotics. These include drugs that are prescribed for therapeutic reasons or chemicals to which women are exposed unintentionally from the surrounding environment. The pregnancy physiologically-based pharmacokinetic (p-PBPK) models developed for theoretical assessment of the kinetics of xenobiotics during pregnancy should take into account all the dynamic changes of the maternal and embryonic/foetal physiological functions. A number of p-PBPK models have been reported for pregnant animals and humans in the past 3 decades which have mainly been applied in the risk assessment of various environmental chemicals. The purpose of this review is to critically evaluate the current state of the art in p-PBPK modelling and to recommend potential steps that could be taken to improve model development and its application particularly in drug discovery and development for pregnant women, with potential implications for optimal drug treatment in pregnancy. The pregnancy-induced changes in physiology and pharmacokinetics, including metabolism, are reviewed to illustrate the basic alterations essential for pregnancy model development. A systemic search of the literature for existing p-PBPK models is carried out and the model structures, governing equations, methods of modelling growth, model validation/verification as well as model applications are highlighted. This review discusses benefits and limitations of the reported p-PBPK models so far and suggests areas for model improvement. The need for establishing databases on the system-related (biological, anatomical and physiological) and drug-related (physiochemical, affinity to enzymes and transpoorters) parameters for healthy and unhealthy pregnancies is particularly emphasized.
妊娠期间母体和胎盘-胎儿单位发生的生理变化会影响外源性物质（包括因治疗目的而开处的药物和妇女因周围环境而意外接触的化学物质）的吸收、分布、代谢和排泄（ADME）。为了理论评估妊娠期间外源性物质的动力学，开发了基于妊娠生理的药代动力学（p-PBPK）模型，这些模型应考虑母体和胚胎/胎儿生理功能的所有动态变化。过去 30 年来，已经为妊娠动物和人类开发了许多 p-PBPK 模型，这些模型主要应用于各种环境化学物质的风险评估。本文的目的是批判性地评估当前 p-PBPK 建模的现状，并提出可能的步骤，以改善模型的开发和应用，特别是在为孕妇开发药物方面，这可能对妊娠期间的最佳药物治疗产生影响。本文回顾了妊娠引起的生理学和药代动力学变化，包括代谢，以说明妊娠模型开发所必需的基本改变。对现有 p-PBPK 模型进行了系统性文献检索，重点介绍了模型结构、控制方程、生长建模方法、模型验证/验证以及模型应用。本文讨论了迄今为止报告的 p-PBPK 模型的优缺点，并提出了改进模型的领域。特别强调需要建立关于健康和不健康妊娠的与系统相关（生物学、解剖学和生理学）和与药物相关（生理化学、与酶和转运蛋白的亲和力）参数的数据库。
