Chen Yuan-Cheng, Liang Wang, Hu Jia-Li, He Gao-Li, Wu Xiao-Jie, Liu Xiao-Fang, Zhang Jing, Hu Xue-Qian
Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, 200040, China.
J Pharmacokinet Pharmacodyn. 2015 Feb;42(1):33-43. doi: 10.1007/s10928-014-9396-7. Epub 2014 Oct 30.
The aim of this paper was to propose a method of flow rate modulation for simulation of in vivo pharmacokinetic (PK) model with intravenous injection based on a basic in vitro PK model. According to the rule of same relative change rate of concentration per unit time in vivo and in vitro, the equations for flow rate modulation were derived using equation method. Four examples from literature were given to show the application of flow rate modulation in the simulation of PK model of antimicrobial agents in vitro. Then an experiment was performed to confirm the feasibility of flow rate modulation method using levo-ornidazole as an example. The accuracy and precision of PK simulations were evaluated using average relative deviation (ARD), mean error and root mean squared error. In vitro model with constant flow rate could mimic one-compartment model, while the in vitro model with decreasing flow rate could simulate the linear mammillary model with multiple compartments. Zero-order model could be simulated using the in vitro model with elevating flow rate. In vitro PK model with gradually decreasing flow rate reproduced the two-compartment kinetics of levo-ornidazole quite well. The ARD was 0.925 % between in vitro PK parameters and in vivo values. Results suggest that various types of PK model could be simulated using flow rate modulation method without modifying the structure. The method provides uniform settings for the simulation of linear mammillary model and zero-order model based on in vitro one-compartment model, and brings convenience to the pharmacodynamic study.
本文旨在基于基础体外药代动力学（PK）模型，提出一种用于模拟静脉注射体内PK模型的流速调节方法。根据体内和体外单位时间内浓度相对变化率相同的规律，采用方程法推导了流速调节方程。给出了文献中的四个实例，以展示流速调节在体外抗菌药物PK模型模拟中的应用。然后以左旋奥硝唑为例进行实验，以证实流速调节方法的可行性。使用平均相对偏差（ARD）、平均误差和均方根误差评估PK模拟的准确性和精密度。恒流速体外模型可模拟单室模型，而流速降低的体外模型可模拟多室线性乳突模型。使用流速升高的体外模型可模拟零级模型。流速逐渐降低的体外PK模型很好地再现了左旋奥硝唑的双室动力学。体外PK参数与体内值之间的ARD为0.925%。结果表明，无需修改结构，使用流速调节方法可模拟各种类型的PK模型。该方法为基于体外单室模型模拟线性乳突模型和零级模型提供了统一设置，为药效学研究带来了便利。
