Application of physiologically based pharmacokinetic modeling to predict acetaminophen metabolism and pharmacokinetics in children.
Application of physiologically based pharmacokinetic modeling to predict acetaminophen metabolism and pharmacokinetics in children.
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DOI：
10.1038/psp.2013.55
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发表时间：
2013-10-16
影响因子：
3.5
通讯作者：
Schmidt, S
中科院分区：
文献类型：
--
作者：
Jiang, X-L;Zhao, P;Barrett, J S;Lesko, L J;Schmidt, S
对乙酰氨基酚（Acetaminophen，APAP）是一种广泛应用的镇痛和解热药物，其代谢过程主要为I相和II相代谢。为了更好地了解这一过程的动力学，并表征儿童和成人之间代谢和药代动力学（PK）的动态变化，我们开发了一种基于生理学的APAP PK（PBPK）模型，将计算机模拟、体外和体内PK数据整合到一个模型中。该模型是为成人开发和合格的，随后通过考虑从出生到成熟的变化，扩大到儿童的应用。一旦开发和合格，它就能够预测静脉和口服APAP后新生儿（0-28天）、婴儿（29天至<2岁）、儿童（2至<12岁）和青少年（12-17岁）的临床PK数据。该方法代表了在缺乏儿科PK信息的情况下，通过PBPK建模使用成人和儿童的既往药物和系统特异性信息预测儿童药物暴露的一般策略。
Acetaminophen (APAP) is a widely used analgesic and antipyretic drug that undergoes extensive phase I and II metabolism. To better understand the kinetics of this process and to characterize the dynamic changes in metabolism and pharmacokinetics (PK) between children and adults, we developed a physiologically based PK (PBPK) model for APAP integrating in silico, in vitro, and in vivo PK data into a single model. The model was developed and qualified for adults and subsequently expanded for application in children by accounting for maturational changes from birth. Once developed and qualified, it was able to predict clinical PK data in neonates (0–28 days), infants (29 days to <2 years), children (2 to <12 years), and adolescents (12–17 years) following intravenous and orally administered APAP. This approach represents a general strategy for projecting drug exposure in children, in the absence of pediatric PK information, using previous drug- and system-specific information of adults and children through PBPK modeling.