Development of a Physiologically-Based Pharmacokinetic Model for Preterm Neonates: Evaluation with In Vivo Data
Development of a Physiologically-Based Pharmacokinetic Model for Preterm Neonates: Evaluation with In Vivo Data
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DOI：
10.2174/1381612821666150901110533
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发表时间：
2015-01-01
影响因子：
3.1
通讯作者：
Willmann, Stefan
中科院分区：
文献类型：
--
作者：
Claassen, Karina;Thelen, Kirstin;Willmann, Stefan
在儿科患者中，早产儿和新生儿是最脆弱的亚群。影响新生儿中原料药药代动力学的生理因素的快速发育变化需要在剂量和给药方案决策中极其谨慎。这些决定可以通过计算机模拟方法（如基于生理学的药代动力学（PBPK）建模）来支持。在一项全面的文献检索中，总结了建立PBPK模型所需的早产儿生理信息，并将其纳入通用PBPK软件的数据库中。生理参数包括器官重量和血液流速、组织组成以及关于肝脏和肾脏中代谢和消除过程的个体发育信息。这项工作的目的是评估该模型的准确性，在预测两种模型药物静脉给药后的药代动力学具有不同的物理化学性质和消除途径的基础上，早期报道的体内数据。为此，已建立丁胺卡那霉素和扑热息痛的PBPK模型来预测早产儿中它们的血浆浓度。将预测的血浆浓度-时间曲线与实验获得的体内数据进行比较。对于这两种药物，单次和多次给药后的血药浓度-时间曲线在大范围的妊娠和出生后年龄中得到了适当预测。总之，早产儿中的PBPK模拟似乎是可行的，并且可能在未来成为支持该特殊患者人群的给药决策的有用工具。
Among pediatric patients, preterm neonates and newborns are the most vulnerable subpopulation. Rapid developmental changes of physiological factors affecting the pharmacokinetics of drug substances in newborns require extreme care in dose and dose regimen decisions. These decisions could be supported by in silico methods such as physiologically-based pharmacokinetic (PBPK) modeling. In a comprehensive literature search, the physiological information of preterm neonates that is required to establish a PBPK model has been summarized and implemented into the database of a generic PBPK software. Physiological parameters include the organ weights and blood flow rates, tissue composition, as well as ontogeny information about metabolic and elimination processes in the liver and kidney. The aim of this work is to evaluate the model's accuracy in predicting the pharmacokinetics following intravenous administration of two model drugs with distinct physicochemical properties and elimination pathways based on earlier reported in vivo data. To this end, PBPK models of amikacin and paracetamol have been set up to predict their plasma levels in preterm neonates. Predicted plasma concentration-time profiles were compared to experimentally obtained in vivo data. For both drugs, plasma concentration-time profiles following single and multiple dosing were appropriately predicted for a large range gestational and postnatal ages. In summary, PBPK simulations in preterm neonates appear feasible and might become a useful tool in the future to support dosing decisions in this special patient population.