Department of Pharmaceutical and Medical Chemistry, Clinical Pharmacy, University of Münster, Corrensstr. 48, 48149, Münster, Germany.
Cancer Chemother Pharmacol. 2013 Nov;72(5):991-1000. doi: 10.1007/s00280-013-2275-x. Epub 2013 Sep 6.
A physiologically based pharmacokinetic (PBPK) model was established and evaluated describing the pharmacokinetics (PK) of the DNA-alkylating agent Busulfan in adults in order to predict the systemic Busulfan drug exposure in both plasma and toxicity-related organs.
A generic PBPK model was tailored to describe Busulfan PK by implementing compound-specific physicochemical and metabolism data. With regard to possible influences of glutathione S transferase (GST) variations on Busulfan PK, two different PBPK model parameterizations were investigated: a first parameterization with individual GST activity (expressed as different estimated V(max) values) for each patient, and a resulting second model parameterization with a mean GST activity for all patients. Simulations were computed and compared to concentration-time data after intravenous Busulfan administration to 108 adults serving as development dataset. Subsequently, appropriateness of the PBPK model was evaluated with an external dataset not used for model development, consisting of 95 adults.
Both PBPK model parameterizations of Busulfan successfully described the observed plasma concentrations. For the validation dataset, calculated PK parameters were as follows: clearance 0.16 ± 0.03 L/h/kg and volume of distribution 0.65 ± 0.06 L/kg (mean ± standard deviation). Mean absolute percentage error was less than 30 % for each PK parameter. Mass balances for distribution and excretion were in good agreement with the literature data.
Both PBPK model parameterizations sufficiently described the observed concentration-time data while showing an adequate predictive performance. The model should be further evaluated for its ability to explain the between-subject variability in intravenous Busulfan PK parameters.
建立并评估了一种基于生理学的药代动力学（PBPK）模型，以描述成人中烷化剂白消安的药代动力学（PK），从而预测血浆和毒性相关器官中白消安的全身药物暴露。
通过实施化合物特异性理化性质和代谢数据，定制了一种通用的 PBPK 模型以描述白消安 PK。考虑到谷胱甘肽 S 转移酶（GST）变异对白消安 PK 的可能影响，对两种不同的 PBPK 模型参数化进行了研究：一种参数化是为每个患者分别表达不同的 GST 活性（表示为不同的估计 Vmax 值），另一种是为所有患者的平均 GST 活性的参数化。模拟计算并与 108 名成人的静脉注射白消安后获得的浓度-时间数据进行比较，作为开发数据集。随后，使用未用于模型开发的外部数据集（包括 95 名成人）评估 PBPK 模型的适当性。
两种白消安 PBPK 模型参数化均成功描述了观察到的血浆浓度。对于验证数据集，计算的 PK 参数如下：清除率为 0.16 ± 0.03 L/h/kg，分布体积为 0.65 ± 0.06 L/kg（平均值 ± 标准差）。每个 PK 参数的平均绝对百分比误差小于 30%。分布和排泄的质量平衡与文献数据吻合良好。
两种 PBPK 模型参数化均充分描述了观察到的浓度-时间数据，同时显示出适当的预测性能。应进一步评估该模型解释静脉内白消安 PK 参数的个体间变异性的能力。
