Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Münster, Münster, Germany.
Cancer Chemother Pharmacol. 2012 Feb;69(2):397-405. doi: 10.1007/s00280-011-1706-9. Epub 2011 Jul 26.
To evaluate the ability of a physiology-based pharmacokinetic (PBPK) model to predict the systemic drug exposure of high- and low-dose etoposide in children from a model developed with adult data.
Simulations were performed with PK-Sim(®) (Bayer Technology Services). Model development was done using data from adult patients receiving etoposide in a conventional and high-dose polychemotherapy regimen before stem cell transplantation. Michaelis-Menten parameters from in vitro experiments reported in the literature were applied to describe the metabolism and excretion processes by P450 enzymes and transporters. The model was scaled down to children and compared to etoposide plasma concentrations in this age group.
Simulated plasma concentration-time courses of protein-bound and free etoposide in adults for high- and low-dose schedules agreed with the observed data. Mean simulated total clearance of high- and low-dose etoposide was 0.70 ml/min/kg (Cl(observed): 0.70 ml/min/kg) versus 0.50 ml/min/kg (Cl(observed): 0.60 ml/min/kg), respectively. Integrated Michaelis-Menten kinetics was adequately transformed to age-related pharmacokinetics in children. Predictions of the pharmacokinetics in different age groups were also in good agreement with observed data. Drug interactions triggered by P-glycoprotein inhibitors or nephrotoxic drugs can also be elucidated.
The PBPK model matched the pharmacokinetics in different dosing regimens in adults. Furthermore, the scaling procedure from the adult model to children provides useful predictions for paediatric patients. Comedication with drugs influencing the metabolism and excretion has to be taken into account. This approach could be useful for planning pharmacokinetic studies in children.
评估基于生理学的药代动力学（PBPK）模型预测儿童高、低剂量依托泊苷系统药物暴露的能力，该模型是使用成人数据开发的。
使用 PK-Sim（®）（拜耳技术服务公司）进行模拟。模型开发是使用接受常规和高剂量联合化疗方案在干细胞移植前接受依托泊苷的成人患者的数据完成的。应用文献中报道的体外实验的米氏-门限参数来描述 P450 酶和转运体的代谢和排泄过程。该模型按比例缩小到儿童，并与该年龄组的依托泊苷血浆浓度进行比较。
高、低剂量方案下成人模拟的蛋白结合和游离依托泊苷的血浆浓度-时间曲线与观察到的数据相符。高、低剂量依托泊苷模拟的总清除率分别为 0.70 ml/min/kg（Cl（观察）：0.70 ml/min/kg）和 0.50 ml/min/kg（Cl（观察）：0.60 ml/min/kg）。整合的米氏-门限动力学被充分转化为儿童的年龄相关药代动力学。不同年龄组的药代动力学预测也与观察到的数据相符。也可以阐明由 P-糖蛋白抑制剂或肾毒性药物引发的药物相互作用。
PBPK 模型与成人不同剂量方案的药代动力学相匹配。此外，从成人模型到儿童的缩放过程为儿科患者提供了有用的预测。必须考虑影响代谢和排泄的合并用药。这种方法可用于计划儿童的药代动力学研究。
