Pharmacokinetic/pharmacodynamic (PK/PD) models predict the effect time course resulting from a drug dose. In this review, we summarize the development of mechanistic PK/PD models that explicitly integrate the kinetics of drug-target interactions into predictions of drug activity. Such mechanistic models are expected to have several advantages over approaches in which concentration and effect are linked using variations of the Hill equation, and where preclinical data are often used as a starting point for modeling drug activity. Instead, explicit use of the full kinetic scheme for drug binding enables time-dependent changes in target occupancy to be calculated using the kinetics of drug-target interactions and drug PK, providing a more precise picture of target engagement and drug action in the non-equilibrium environment of the human body. The mechanistic PK/PD models also generate target vulnerability functions that link target occupancy and effect, and inform on the sensitivity of a target to engagement by a drug. Key factors such as the rate of target turnover can also be integrated into the modeling which, together with target vulnerability, provide additional information on the PK profile required to achieve the desired pharmacological effect and on the utility of kinetic selectivity in developing drugs for specific targets.

中文翻译：

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结合了药物-靶标结合动力学的药代动力学-药效学模型。

药代动力学/药效学（PK / PD）模型可预测药物剂量产生的作用时间。在这篇综述中，我们总结了机制性PK / PD模型的开发，该模型将药物-靶标相互作用的动力学明确整合到药物活性的预测中。与使用Hill方程的变化将浓度和作用联系在一起的方法以及临床前数据通常用作建模药物活性的起点时，这种机制模型有望具有多种优势。取而代之的是，将完整的动力学方案明确用于药物结合，可以使用药物-靶标相互作用和药物PK的动力学来计算靶标占用时间的时间依赖性变化，从而在非人体的平衡环境。机械PK / PD模型还生成目标易损性功能，这些功能将目标的占有率和效果联系起来，并告知目标对药物参与的敏感性。诸如目标转换率之类的关键因素也可以集成到模​​型中，该模型与目标脆弱性一起，提供有关实现所需药理作用所需的PK谱以及在开发针对特定目标的药物中动力学选择性的实用性的其他信息。