El-Kareh Ardith W, Labes Rachel E, Secomb Timothy W
ARL-Microcirculation Division, University of Arizona, PO Box 245051, Tucson, AZ 85724-5051, USA.
AAPS J. 2008;10(1):15-34. doi: 10.1208/s12248-007-9003-6. Epub 2008 Feb 5.
A pharmacokinetic-pharmacodynamic mathematical model is developed for cellular pharmacology of chemotherapeutic drugs for which the decisive step towards cell death occurs at a point in the cell cycle, presumably corresponding to a cell cycle checkpoint. For each cell, the model assumes a threshold level of some intracellular species at that checkpoint, beyond which the cell dies. The threshold level is assumed to have a log-normal distribution in the cell population. The kinetics of formation of the lethal intracellular species depends on the drug, and on the cellular pharmacokinetics and binding kinetics of the cell. Specific models are developed for paclitaxel and for platinum drugs (cisplatin, oxaliplatin and carboplatin). In the case of paclitaxel, two separate mechanisms of cell death necessitate a model that accounts for two checkpoints, with different intracellular species. The model was tested on a number of in vitro cytotoxicity data sets for these drugs, and found overall to give significantly better fits than previously proposed cellular pharmacodynamic models. It provides an explanation for the asymptotic convergence of dose-response curves as exposure time becomes long.
针对化疗药物的细胞药理学，建立了一个药代动力学 - 药效学数学模型。对于这类药物，细胞死亡的决定性步骤发生在细胞周期的某个点，大概对应于一个细胞周期检查点。对于每个细胞，该模型假设在那个检查点存在某种细胞内物质的阈值水平，超过此阈值细胞就会死亡。假设阈值水平在细胞群体中呈对数正态分布。致死性细胞内物质的形成动力学取决于药物、细胞的细胞药代动力学和结合动力学。针对紫杉醇和铂类药物（顺铂、奥沙利铂和卡铂）开发了特定模型。在紫杉醇的情况下，两种不同的细胞死亡机制需要一个考虑两个检查点及不同细胞内物质的模型。该模型在这些药物的多个体外细胞毒性数据集上进行了测试，总体发现其拟合效果比先前提出的细胞药效学模型显著更好。它为暴露时间变长时剂量 - 反应曲线的渐近收敛提供了解释。
