Yao Zhenling, Krzyzanski Wojciech, Jusko William J
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York, Buffalo, NY 14260, USA.
J Pharmacokinet Pharmacodyn. 2006 Apr;33(2):167-93. doi: 10.1007/s10928-006-9003-7.
Many physiological factors are regulated by homeostatic mechanisms to maintain normal body function. Empirical lower Rl (Model I and IV) or upper Rh limits (Model II and III) were included in current basic indirect response (IDR) models to account for the additional role of physiological limits (IDRPL). Various characteristics of these models were evaluated with simulations and explicit equations. The simulations reveal that the expanded models exhibit most properties of basic indirect response models, such as slow response initiation, lag time between the kinetic and dynamic peaks, a large dose plateau, and shift in Tmax with dose. The proposed models always produce lesser net responses than predicted by basic IDR models. Simulations demonstrate that addition of a parameter limit which is close to the baseline has a great influence on the overall and maximum responses and fitted model parameters. Only stimulatory IDRPL Models III and IV allow resolution of all model parameters in the absence of clear indications or predetermined values of the lower or upper limits. However, all four models are able to resolve model parameters when subgroups with different baselines are simultaneously fitted. These models create new interpretations of the determinants of baseline conditions which can be important in assessing inter-subject variability in responses. The applicability of IDRPL models is demonstrated using several examples from the published literature. Indirect response models with physiological limits will be useful in characterizing drug responses for turnover systems which are maintained within a certain range.
许多生理因素通过稳态机制进行调节，以维持身体的正常功能。当前的基本间接响应（IDR）模型纳入了经验性的较低Rl（模型I和IV）或较高Rh限值（模型II和III），以解释生理限值（IDRPL）的额外作用。通过模拟和显式方程对这些模型的各种特性进行了评估。模拟结果表明，扩展后的模型展现出基本间接响应模型的大多数特性，如响应起始缓慢、动力学峰值与动态峰值之间的滞后时间、大剂量平台以及Tmax随剂量的变化。所提出的模型产生的净响应总是低于基本IDR模型的预测值。模拟表明，添加一个接近基线的参数限值对总体和最大响应以及拟合模型参数有很大影响。只有刺激性的IDRPL模型III和IV在没有下限或上限的明确指示或预定值的情况下能够解析所有模型参数。然而，当同时拟合具有不同基线的亚组时，所有四个模型都能够解析模型参数。这些模型对基线条件的决定因素产生了新的解释，这在评估受试者间反应变异性方面可能很重要。通过已发表文献中的几个例子展示了IDRPL模型的适用性。具有生理限值的间接响应模型将有助于表征维持在一定范围内的周转系统的药物反应。
