Prediction of Phase I single-dose pharmacokinetics using recombinant cytochromes P450 and physiologically based modelling
Prediction of Phase I single-dose pharmacokinetics using recombinant cytochromes P450 and physiologically based modelling
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DOI：
10.1080/00498250902954296
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发表时间：
2009-01-01
期刊：
影响因子：
1.8
通讯作者：
Mulrooney, E.
中科院分区：
文献类型：
--
作者：
Gibson, C. R.;Bergman, A.;Mulrooney, E.
1.从默克研究实验室的管道中选择了10种化合物，以评价使用重组表达的细胞色素P450（P450）的固有清除率和基于生理学的药代动力学建模预测I期药代动力学的效用。预计所选化合物主要通过P450代谢消除。预测和实际临床暴露量之间存在合理的一致性，80%的预测暴露量在观察值的3倍范围内。此外，C（t）（特定时间点的血浆浓度）和T（max）的预测可接受，大于或等于70%的预测数据在观察值的3倍范围内。然而，C（max）的预测不可靠，可能是由于预测分布容积随时间变化的误差和/或估计吸收率的误差。尽管人们承认需要研究来提高预测性能，但所提供的数据支持使用重组P450固有清除率和基于生理学的药代动力学建模来预测通过P450代谢消除的化合物的I期药代动力学。
1. Ten compounds from the Merck Research Laboratories pipeline were selected to evaluate the utility of using intrinsic clearance derived from recombinantly expressed cytochromes P450 (CYP) and physiologically based pharmacokinetic modelling to predict Phase I pharmacokinetics using simCYP. The compounds selected were anticipated to be eliminated predominantly by P450 metabolism.2. There was a reasonable agreement between the predicted and actual clinical exposure with 80% of the predicted exposures being within three-fold of the observed values. Furthermore, prediction of C(t) (plasma concentration at a specified time point) and T(max) were acceptable with greater than or equal to 70% of the predicted data being within three-fold of the observed values. However, prediction of C(max) was unreliable and may have been due to error in predicting the time-dependent change in volume of distribution and/or error in estimating absorption rate.3. Although it is acknowledged that research is needed to improve predictive performance, the data presented are supportive of using recombinant P450 intrinsic clearance and physiologically based pharmacokinetic modelling to predict Phase I pharmacokinetics for compounds eliminated by P450 metabolism.