Luu Kenneth T, Uchizono James A
Department of Pharmaceutics and Medicinal Chemistry, University of the Pacific, Stockton, CA 95211, USA.
Pharm Res. 2005 May;22(5):710-5. doi: 10.1007/s11095-005-2585-8. Epub 2005 May 17.
The objectives of this work were 1) to develop a theoretical pharmacodynamic model that captures dynamic changes resulting from drug/therapy mediated P-glycoprotein (P-gp) induction and 2) to compare the pharmacodynamic outcomes of several doxorubicin (DOX) dosing schemes through simulations.
We developed a theoretical model that included a pharmacokinetic (PK) model for intracellular DOX-mediated P-gp induction and a pharmacodynamic (PD) model using a threshold trigger function for tumor cell-kill. In this model, both the level of P-gp induction and rate of tumor cell death were modulated by intracellular DOX concentration. Most model parameters were obtained from literature sources, and a few were either fixed or reasonably estimated.
Comparative dosing simulations showed that a 10-week constant infusion in which a tumor cell population was continuously exposed to the drug did not produce the best PD profile. On the other hand, dosing schemes where the cell population was initially challenged with a high dose, followed by intermittent dosing, generated the best PD profile. The favorable outcome of the latter dosing schemes was correlated with the lowest expression of P-gp in terms of area under the curve (AUC) during treatment period.
The simulations led us to conclude that drug resistance, particularly resistance caused by P-gp overexpression, induced during chemotherapy may, in part, be circumvented by designing optimal dosing strategies that minimize P-gp induction.
本研究的目标是：1）建立一个理论药效学模型，以捕捉药物/治疗介导的P-糖蛋白（P-gp）诱导所导致的动态变化；2）通过模拟比较几种阿霉素（DOX）给药方案的药效学结果。
我们建立了一个理论模型，该模型包括一个用于细胞内DOX介导的P-gp诱导的药代动力学（PK）模型和一个使用阈值触发函数进行肿瘤细胞杀伤的药效学（PD）模型。在这个模型中，P-gp诱导水平和肿瘤细胞死亡率均由细胞内DOX浓度调节。大多数模型参数来自文献，少数参数要么固定要么合理估算。
对比给药模拟显示，对肿瘤细胞群体持续给药10周的恒速输注方案并未产生最佳的药效学特征。另一方面，先给予高剂量初始冲击，然后间歇性给药的方案产生了最佳的药效学特征。后一种给药方案的良好结果与治疗期间曲线下面积（AUC）方面P-gp的最低表达相关。
模拟结果使我们得出结论，化疗期间诱导产生的耐药性，尤其是由P-gp过表达引起的耐药性，部分可通过设计使P-gp诱导最小化的最佳给药策略来规避。
