Department of Laboratory Medicine, Experimental Cancer Medicine, Karolinska Institutet Huddinge, Novum, 141 86, Stockholm, Sweden,
Clin Drug Investig. 2014 Jan;34(1):43-52. doi: 10.1007/s40261-013-0148-z.
Therapeutic drug monitoring (TDM) of the first dose of busulphan during conditioning prior to allogeneic stem cell transplantation provides the possibility of improving the clinical outcome via dose adjustment of subsequent doses. The plasma area under the concentration-time curve (AUC) for busulphan is generally accepted as the parameter that gives the best exposure estimate; however, the sampling frequency needed for reliable AUC calculation remains controversial. The aim of the present investigation was to develop and evaluate a limited sampling model for oral busulphan.
We have compared models using three to four samples with standard WinNonlin(®) adaptive compartment modeling based on eight samples as reference. The evaluated study population included both adult and pediatric patients, but the linear model was devised using analysis of only pediatric patient plasma concentrations. The present model was developed using data from 23 patients with a mean age of 38 years (range 13-59 years) and was evaluated in 20 pediatric patients with a mean age of 6 years (range 0.1-13 years) as well as 23 adult patients (mean age 43 years; range 18-67 years).
In 23 patients, the mean AUC from a curve fitting model (Purves method) and a single compartment model had an intraclass correlation coefficient (ICC) of 0.947. From a log-log plot of AUC values it was evident that using this estimate of the AUC would affect dose adjustment decisions for very few of the patients. Applying the linear model using three samples resulted in an ICC of 0.932, mostly due to worse performance in the adult population.
The present results support the use of limited sampling in clinical TDM for oral busulphan provided adequate algorithms and sampling times are used. Moreover, they also demonstrate the caution that is needed when transferring a pharmacokinetic model from a pediatric population to an adult population.
异基因造血干细胞移植前预处理时首剂马法兰的治疗药物监测（TDM）可通过调整后续剂量来提高临床疗效。马法兰的血药浓度-时间曲线下面积（AUC）通常被认为是反映暴露量的最佳参数，但可靠计算 AUC 所需的采样频率仍存在争议。本研究旨在建立和评估口服马法兰的有限采样模型。
我们比较了使用三到四个样本的模型与基于 8 个样本的标准 WinNonlin（®）自适应室模型，后者作为参考。评估的研究人群包括成人和儿科患者，但线性模型是使用仅儿科患者血浆浓度分析设计的。本模型是在 23 名平均年龄 38 岁（13-59 岁）的患者数据的基础上开发的，随后在 20 名平均年龄 6 岁（0.1-13 岁）的儿科患者和 23 名平均年龄 43 岁（18-67 岁）的成年患者中进行了评估。
在 23 名患者中，曲线拟合模型（Purves 法）和单室模型的 AUC 均值的组内相关系数（ICC）为 0.947。AUC 值的对数-对数图表明，使用这种 AUC 估计值将影响极少数患者的剂量调整决策。使用三个样本的线性模型导致 ICC 为 0.932，这主要是由于成人患者的表现较差。
本研究结果支持在口服马法兰的临床 TDM 中使用有限采样，前提是使用适当的算法和采样时间。此外，它们还表明在将药代动力学模型从儿科人群转移到成人人群时需要谨慎。
