Maitre P O, Bührer M, Thomson D, Stanski D R
Department of Anesthesiology and Intensive Care, University of Bern, Inselspital, Switzerland.
J Pharmacokinet Biopharm. 1991 Aug;19(4):377-84. doi: 10.1007/BF01061662.
NONMEM, the only available supported program for population pharmacokinetic analysis, does not provide the analyst with individual subject parameter estimates. As a result, the relationship between pharmacokinetic parameters and demographic factors such as age, gender, and body weight cannot be sought by plotting demographic factors vs. kinetic parameters. To overcome this problem, we devised a three-step approach. In step 1, an initial NONMEM analysis provides the population pharmacokinetic parameters without taking into account the demographic factors. Step 2 consists of individual bayesian regressions using the measured drug concentrations for each subject and the population pharmacokinetic parameters obtained in step 1. The bayesian parameter estimates of the individual subject can be plotted against the demographic factors of interest. From the scatter plots, it can be seen which are the demographic factors that appear to affect the pharmacokinetic parameters. In step 3, the NONMEM analysis is resumed, and the demographic factors found in step 2 are entered into the NONMEM regression model in a stepwise manner. This method was used to analyze the pharmacokinetics of midazolam in 64 subjects from 714 plasma concentrations and 11 demographic factors. CL (elimination clearance) and V1 were found to be a function of body weight. Age and liver disease were found to decrease CL. Of the 11 demographic factors recorded for each patient, none was found to influence VSS or intercompartmental clearance.
NONMEM是唯一可用于群体药代动力学分析的受支持程序，但它无法为分析人员提供个体受试者的参数估计值。因此，无法通过绘制人口统计学因素与动力学参数的关系图来探寻药代动力学参数与年龄、性别和体重等人口统计学因素之间的关系。为克服这一问题，我们设计了一种三步法。第一步，进行初始的NONMEM分析，在不考虑人口统计学因素的情况下提供群体药代动力学参数。第二步包括使用每个受试者的实测药物浓度以及第一步中获得的群体药代动力学参数进行个体贝叶斯回归。个体受试者的贝叶斯参数估计值可以与感兴趣的人口统计学因素进行绘制。从散点图中，可以看出哪些人口统计学因素似乎会影响药代动力学参数。第三步，恢复NONMEM分析，并将第二步中发现的人口统计学因素逐步纳入NONMEM回归模型。该方法用于分析64名受试者中咪达唑仑的药代动力学，数据来自714个血浆浓度和11个人口统计学因素。发现清除率（CL）和中央室分布容积（V1）是体重的函数。发现年龄和肝病会降低CL。在为每位患者记录的11个人口统计学因素中，未发现有因素会影响稳态分布容积（VSS）或隔室间清除率。
