Clewell H J, Lee T S, Carpenter R L
Clement Associates, Ruston, Louisiana.
Risk Anal. 1994 Aug;14(4):521-31. doi: 10.1111/j.1539-6924.1994.tb00268.x.
The parameters in a physiologically based pharmacokinetic (PBPK) model of methylene chloride were varied systematically, and the resulting variation in a number of model outputs was determined as a function of time for mice and humans at several exposure concentrations. The importance of the various parameters in the model was highly dependent on the conditions (concentration, species) for which the simulation was performed and the model output (dose surrogate) being considered. Model structure also had a significant impact on the results. For sensitivity analysis, particular attention must be paid to conservation equations to ensure that the variational calculations do not alter mass balance, introducing extraneous effects into the model. All of the normalized sensitivity coefficients calculated in this study ranged between -1.12 and 1, and most were much less than 1 in absolute value, indicating that individual input errors are not greatly amplified in the outputs. In addition to ranking parameters in terms of their impact on model predictions, time-dependent sensitivity analysis can also be used as an aid in the design of experiments to estimate parameters by predicting the experimental conditions and sampling points which will maximize parameter identifiability.
对二氯甲烷基于生理的药代动力学（PBPK）模型中的参数进行了系统变化，并确定了在几种暴露浓度下，小鼠和人类的一些模型输出随时间变化的结果。模型中各个参数的重要性高度依赖于进行模拟的条件（浓度、物种）以及所考虑的模型输出（剂量替代指标）。模型结构对结果也有显著影响。对于敏感性分析，必须特别注意守恒方程，以确保变分计算不会改变质量平衡，从而不会将无关效应引入模型。本研究中计算的所有归一化敏感性系数介于 -1.12 和 1 之间，且大多数绝对值远小于 1，这表明单个输入误差在输出中不会被大幅放大。除了根据参数对模型预测的影响进行排序外，时间依赖性敏感性分析还可用于辅助实验设计，通过预测能使参数可识别性最大化的实验条件和采样点来估计参数。
