Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies
Implementation of a transit compartment model for describing drug absorption in pharmacokinetic studies
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DOI：
10.1007/s10928-007-9066-0
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发表时间：
2007-10-01
影响因子：
2.5
通讯作者：
Karlsson, Mats O.
中科院分区：
文献类型：
--
作者：
Savic, Radojka M.;Jonker, Danieel M.;Karlsson, Mats O.
目的：在评价4种不同化合物的4项药代动力学研究中，比较标准滞后时间模型（LAG模型）与转运室模型（TRANSIT模型）分析解的性能。研究方法：使用NONMEM对格列本脲、呋塞米、阿米洛利和莫索尼定的浓度-时间数据进行群体药代动力学分析。在TRANSIT模型中，根据数据估计了最佳的中转车厢数量。这是基于一系列转运隔室引起的药物浓度变化的分析溶液，每个隔室之间具有相同的一级转移速率。拟合优度通过目标函数值（OFV）的降低和诊断图的检查进行评估。结果如下：对于所有药物，与LAG模型相比，TRANSIT模型在吸收阶段的OFV显著降低，拟合优度显著提高。两种模型之间与吸收相关的参数估计值不同，而药代动力学分布参数的估计值相似。结论：基于这些结果，TRANSIT模型是一个有吸引力的替代建模药物吸收延迟，特别是当一个LAG模型描述不佳的药物吸收阶段或数值不稳定。
Purpose: To compare the performance of the standard lag time model (LAG model) with the performance of an analytical solution of the transit compartment model (TRANSIT model) in the evaluation of four pharmacokinetic studies with four different compounds. Methods: The population pharmacokinetic analyses were performed using NONMEM on concentration-time data of glibenclamide, furosemide, amiloride, and moxonidine. In the TRANSIT model, the optimal number of transit compartments was estimated from the data. This was based on an analytical solution for the change in drug concentration arising from a series of transit compartments with the same first-order transfer rate between each compartment. Goodness-of-fit was assessed by the decrease in objective function value (OFV) and by inspection of diagnostic graphs. Results: With the TRANSIT model, the OFV was significantly lower and the goodness-of-fit was markedly improved in the absorption phase compared with the LAG model for all drugs. The parameter estimates related to the absorption differed between the two models while the estimates of the pharmacokinetic disposition parameters were similar. Conclusion: Based on these results, the TRANSIT model is an attractive alternative for modeling drug absorption delay, especially when a LAG model poorly describes the drug absorption phase or is numerically unstable.