Abstract：
Indirect response (IDR) and turnover with inactivation (TI) comprise two arrays of mechanism-based pharmacodynamic (PD) models widely used to describe delayed drug effects. IDR Model-IV (stimulation of response loss) and TI (irreversible loss) have been described with discerning \"signature\" profiles; classical IDR-IV response-time profiles display slow declines where peak response shifts later with increasing dose, whereas TI profiles feature steep response declines with earlier-shifting nadirs. Herein, we demonstrate mathematical convergence of IDR-IV and TI models upon implementation with identical linear versus nonlinear pharmacologic effect terms. Time of peak response in IDR-IV can in fact shift earlier or later depending on PK or PD parameters (e.g., kel, Smax) and effect type. A generalized dynamic model linking mRNA and protein turnover is proposed. Applicability of IDR-IV and TI, with either linear or nonlinear terms acting on degradation/catabolism/loss of response, is demonstrated through model-fitting PK-PD effects of three proteolysis-targeting chimeras (PROTACs) and two ligand-conjugated small interfering RNAs (siRNA). This work clarifies mathematical properties, convergence, and expected responses of IDR-IV and TI, demonstrates their applicability for targeted gene-silencing and protein-degrading agents, and illustrates how well-designed in vivo studies covering broad dose ranges with richly sampled time-points can influence PK-PD model structure and parameter resolution.
摘要：
间接反应（IDR）和失活转化（TI）包括两个基于机制的药效学（PD）模型阵列，广泛用于描述延迟的药物作用。IDR模型-IV（刺激反应损失）和TI（不可逆损失）已被描述为具有明显的“特征”曲线；典型的IDR-IV反应时间曲线显示缓慢下降，其中最小反应随剂量增加而变化，而TI配置文件的特点是响应急剧下降与较早移动的最低点。在这里，我们证明了IDR-IV和TI模型在使用相同的线性和非线性药理作用项实施时的数学收敛性.实际上，根据PK或PD参数，IDR-IV中的峰值响应时间可以更早或更晚移动（例如，Kel,Smax)和效果类型。提出了连接mRNA和蛋白质周转的广义动态模型。IDR-IV和TI的适用性，线性或非线性项作用于降解/分解代谢/响应损失，通过模型拟合三种蛋白水解靶向嵌合体(PROTACs)和两种配体缀合的小干扰RNA(siRNA)的PK/PD效应来证明。这项工作阐明了数学性质，收敛,以及IDR-IV和TI的预期反应，证明了它们对靶向基因沉默和蛋白质降解剂的适用性，并说明了设计良好的体内研究如何覆盖广泛的剂量范围和丰富的采样时间点可以影响PK-PD模型的结构和参数分辨率。
