Hepatic Clearance Predictions from In Vitro-In Vivo Extrapolation and the Biopharmaceutics Drug Disposition Classification System
Hepatic Clearance Predictions from In Vitro-In Vivo Extrapolation and the Biopharmaceutics Drug Disposition Classification System
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DOI：
10.1124/dmd.116.071514
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发表时间：
2016-11-01
影响因子：
3.9
通讯作者：
Benet, Leslie Z.
中科院分区：
文献类型：
--
作者：
Bowman, Christine M.;Benet, Leslie Z.
根据体外数据预测体内药代动力学参数（如清除率）是药物开发过程的关键部分。有一个经常被引用的趋势是，高度蛋白质结合的药物和肝脏摄取转运蛋白的底物通常产生最坏的预测。基于这些信息，研究人员评估了使用人微粒体和肝细胞的11种不同数据集，以寻找准确性、蛋白质结合程度和基于生物制药药物处置分类系统（BDDCS）的药物分类趋势，该系统可以预测转运体的作用。如前所述，体外系统（微粒体和肝细胞）给出了大量不准确的结果，定义为预测值低于体内值的2倍以上。准确率的加权平均值为66.5%。与1类化合物不同，BDDCS 2类药物在体内受转运体效应的影响，因此预测不准确的比例更高，通常偏差略大。然而，由于两个类别的不准确性百分比的加权平均值仍然很高（类别2为81.9%，类别1为62.3%），因此目前可能难以使用BDDCS类别来预测潜在的准确性。本研究的结果强调需要改进体外到体内的外推实验方法，因为使用基于生理的缩放仍然不准确，BDDCS目前无法帮助预测准确的结果。
Predicting in vivo pharmacokinetic parameters such as clearance from in vitro data is a crucial part of the drug-development process. There is a commonly cited trend that drugs that are highly protein-bound and are substrates for hepatic uptake transporters often yield the worst predictions. Given this information, 11 different data sets using human microsomes and hepatocytes were evaluated to search for trends in accuracy, extent of protein binding, and drug classification based on the Biopharmaceutics Drug Disposition Classification System (BDDCS), which makes predictions about transporter effects. As previously reported, both in vitro systems (microsomes and hepatocytes) gave a large number of inaccurate results, defined as predictions falling more than 2-fold outside of in vivo values. The weighted average of the percentage of inaccuracy was 66.5%. BDDCS class 2 drugs, which are subject to transporter effects in vivo unlike class 1 compounds, had a higher percentage of inaccurate predictions and often had slightly larger bias. However, since the weighted average of the percentage of inaccuracy was still high in both classes (81.9% for class 2 and 62.3% for class 1), it may be currently hard to use BDDCS class to predict potential accuracy. The results of this study emphasize the need for improved in vitro to in vivo extrapolation experimental methods, as using physiologically based scaling is still not accurate, and BDDCS cannot currently help predict accurate results.