Evaluation of a basic physiologically based pharmacokinetic model for simulating the first-time-in-animal study
Evaluation of a basic physiologically based pharmacokinetic model for simulating the first-time-in-animal study
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DOI：
10.1016/j.ejps.2007.03.008
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发表时间：
2007-07-01
影响因子：
4.6
通讯作者：
Poggesi, Italo
中科院分区：
文献类型：
--
作者：
Germani, Massimiliano;Crivori, Patrizia;Poggesi, Italo
本研究的目的是评价一种基于生理学的药代动力学（PBPK）方法，用于预测啮齿动物静脉给药候选药物后预期的血药浓度-时间曲线。这些预测是基于少量的性质，这些性质是基于候选药物的结构（辛醇：水分配系数，电离常数）计算的，或者是从早期药物发现阶段实施的典型高通量筛选中获得的（血浆中未结合的分数和肝脏固有清除率）。对模型进行了测试，比较了45种分子的预测和观察到的药代动力学。该数据集包括来自不同发现项目的6种已知药物和39种候选药物，因此可以在真实的发现案例中评估模型的性能。预测的血浆浓度-时间曲线具有良好的准确性，药代动力学参数平均为实际值的2 - 3倍。多变量分析用于识别可能与有偏预测相关的候选属性。发现这种方法的应用对于体内药代动力学筛选的优先级排序和首次动物研究的设计是有用的。(c)2007 Elsevier B. V.保留所有权利。
The objective of this study was to evaluate a physiologically based pharmacokinetic (PBPK) approach for predicting the plasma concentration-time curves expected after intravenous administration of candidate drugs to rodents. The predictions were based on a small number of properties that were either calculated based on the structure of the candidate drug (octanol:water partition coefficient, ionization constant(s)) or obtained from the typical high-throughput screens implemented in the early drug discovery phases (fraction unbound in plasma and hepatic intrinsic clearance). The model was tested comparing the predicted and the observed pharmacokinetics of 45 molecules. This dataset included six known drugs and 39 drug candidates from different discovery programs, so that the performance of the model could be evaluated in a real discovery case scenario. The plasma concentration-time curves were predicted with good accuracy, the pharmacokinetic parameters being on average two- to three-fold of actual values. Multivariate analysis was used for identifying the candidate properties which were likely associated to biased predictions. The application of this approach was found useful for the prioritization of the in vivo pharmacokinetics screens and the design of the first-time-in-animal studies. (c) 2007 Elsevier B.V. All rights reserved.