INRA, UMR 1331, Toxalim, F-31027 Toulouse, France.
Pharm Res. 2011 Aug;28(8):1948-62. doi: 10.1007/s11095-011-0422-9. Epub 2011 Apr 14.
Within-subject dependency of observations has a strong impact on the evaluation of population pharmacokinetic (PK) and/or pharmacodynamic (PD) models. To our knowledge, none of the current model evaluation tools correctly address this issue. We present a new method with a global test and easy diagnostic plot which relies on the use of a random projection technique that allows the analysis of dependent data.
For each subject, the vector of standardised residuals is calculated and projected onto many random directions drawn uniformly from the unit sphere. Our test compares the empirical distribution of projections with their distribution under the model. Simulation studies assess the level of the test and compare its performance with common metrics including normalised prediction distribution errors and different types of weighted residuals. An application to real data is performed.
In contrast to other evaluated methods, our test shows adequate level for all models and designs investigated, which confirms its good theoretical properties. The weakness of other methods is demonstrated and discussed.
This new test appears promising and could be used in combination with other tools to drive model evaluation in population PK/PD analyses.
观察对象内的依存关系对群体药代动力学（PK）和/或药效动力学（PD）模型的评估有很大影响。据我们所知，目前没有一种现有的模型评估工具能够正确解决这个问题。我们提出了一种新的方法，该方法具有全局检验和易于诊断的图形，依赖于使用随机投影技术，允许对相关数据进行分析。
对于每个个体，计算标准化残差向量，并将其投影到许多从单位球均匀抽取的随机方向上。我们的检验将投影的经验分布与模型下的分布进行比较。模拟研究评估了检验的水平，并比较了其与常见指标（包括归一化预测分布误差和不同类型的加权残差）的性能。对真实数据进行了应用。
与其他评估方法相比，我们的检验在所有研究的模型和设计中都显示出了适当的水平，这证实了其良好的理论特性。还展示和讨论了其他方法的弱点。
这种新的检验方法很有前途，可以与其他工具结合使用，以推动群体 PK/PD 分析中的模型评估。
