Diestelhorst Christian, Boos Joachim, McCune Jeannine S, Russell James, Kangarloo S Bill, Hempel Georg
1Department of Pharmaceutical and Medical Chemistry - Clinical Pharmacy, University of Münster, Münster, Germany.
Pediatr Hematol Oncol. 2014 Nov;31(8):731-42. doi: 10.3109/08880018.2014.927945. Epub 2014 Jul 9.
A physiologically based pharmacokinetic (PBPK) model of the DNA-alkylating agent busulfan was slightly modified and scaled from adults to children in order to predict the systemic busulfan drug exposure in children. Capitalizing on the recent major software release of PK-Sim®, we refined our PBPK model by implementing glutathione S transferase (GST) in 11 organs using the software integrated enzyme expression database. In addition, two irreversible binding processes (i.e., DNA and plasma protein binding) were applied by using Koff and KD values. The model was scaled from adults to children. Simulations were computed and compared to concentration-time data after intravenous (i.v.) busulfan administration to 36 children. Based on the results, an age-dependent enzyme activity and maturation ratio was tailored and evaluated with an external dataset consisting of 23 children. Initial adult to children scaling indicated lower clearance values for children in comparison to adults. Subsequent age-dependent maturation ratio resulted in three different age groups: Activity of busulfan-glutathione conjugate formation was 80%, 61%, and 89% in comparison to adults for children with an age of up to 2 years, > 2-6 years, and > 6-18 years, respectively. Patients of the evaluation dataset were simulated with a mean percentage error (MPE) for all patients of 3.9% with 3/23 children demonstrating a MPE of > ±30%. The PBPK model parameterization sufficiently described the observed concentration-time data of the validation dataset while showing an adequate predictive performance. This PBPK model could be helpful to determine the first dose of busulfan in children.
为预测儿童体内白消安的全身药物暴露量，对DNA烷化剂白消安的基于生理的药代动力学（PBPK）模型进行了微调，并按比例从成人模型转换为儿童模型。利用PK-Sim®最近的一次重大软件更新，我们通过使用软件集成酶表达数据库在11个器官中纳入谷胱甘肽S转移酶（GST），对我们的PBPK模型进行了优化。此外，通过使用解离速率常数（Koff）和解离常数（KD）值应用了两个不可逆结合过程（即DNA和血浆蛋白结合）。该模型按比例从成人转换为儿童模型。对36名儿童静脉注射白消安后的浓度-时间数据进行了模拟计算并进行比较。基于这些结果，根据一个由23名儿童组成的外部数据集定制并评估了年龄依赖性酶活性和成熟率。最初从成人到儿童的比例缩放表明，与成人相比，儿童的清除率较低。随后的年龄依赖性成熟率产生了三个不同的年龄组：对于年龄在2岁及以下、大于2至6岁、大于6至18岁的儿童，与成人相比，白消安-谷胱甘肽共轭物形成活性分别为80%、61%和89%。评估数据集中的患者进行模拟时，所有患者的平均百分比误差（MPE）为3.9%，其中3/23名儿童的MPE大于±30%。PBPK模型参数化充分描述了验证数据集观察到的浓度-时间数据，同时显示出足够的预测性能。这个PBPK模型可能有助于确定儿童白消安的首剂量。
