Sallas W M, Nedelman J R, Sheiner L B, Meligeni J A, Robinson W T
Department of Drug Metabolism and Pharmacokinetics, Sandoz Research Institute, Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey 07936, USA.
J Pharmacokinet Biopharm. 1995 Oct;23(5):495-514. doi: 10.1007/BF02353471.
A nonlinear mixed-effects model simultaneously modeled two pharmacokinetic (PK) variables in patients administered cyclosporine twice daily: (i) concentration of drug in blood at the end of the 12-hr dosing interval (C12) and (ii) area under the concentration-time curve within the dosing interval (AUC). For two formulations (Neoral and Sandimmune), the model assessed the following: nonlinearity with respect to dose, interoccasion (intraindividual) variability, interindividual variability, and within- and across-individual correlation between C12 and AUC. Data were pooled from six clinical studies in stable renal transplant patients administered each formulation. PK samples on two occasions were taken usually for each formulation. Each individual's random effect was eight-dimensional consisting of two PK variables for each formulation on two occasions. An ANOVA-like partitioning worked well and reduced the variance matrix for the random effect to a known function of 13 parameters to be estimated, thereby making a numerically intensive computation feasible. Simulations were used to check the model fit, to compute standard errors, and to account for peculiarities in the residual analysis. Outcomes of tests comparing formulations, most of which were statistically significant, favored Neoral (dose proportional, lower interoccasion variability, lower interindividual variability, and higher correlation between C12 and AUC).
一个非线性混合效应模型同时对每天服用两次环孢素的患者的两个药代动力学（PK）变量进行建模：（i）12小时给药间隔结束时血液中的药物浓度（C12）和（ii）给药间隔内浓度-时间曲线下面积（AUC）。对于两种制剂（新山地明和山地明），该模型评估了以下内容：剂量的非线性、不同给药 occasion（个体内）变异性、个体间变异性以及C12和AUC之间的个体内和个体间相关性。数据来自六项针对接受每种制剂治疗的稳定肾移植患者的临床研究。通常每种制剂采集两次PK样本。每个个体的随机效应是八维的，由两次每种制剂的两个PK变量组成。类似方差分析的划分效果良好，并将随机效应的方差矩阵简化为一个待估计的13个参数的已知函数，从而使数值密集型计算可行。模拟用于检查模型拟合、计算标准误差以及考虑残差分析中的特殊性。比较制剂的测试结果大多具有统计学意义，支持新山地明（剂量成比例、较低的不同给药occasion变异性、较低的个体间变异性以及C12和AUC之间较高的相关性）。
