Department of Clinical Pharmacy, University Medical Center, Utrecht, the Netherlands.
Ther Drug Monit. 2012 Oct;34(5):574-83. doi: 10.1097/FTD.0b013e31826051bb.
Recently a pediatric pharmacokinetic (PK) model was developed for busulfan to explain the wide variability in PK of busulfan in children, as this variability is known to influence the outcome of hematopoietic stem cell transplantation in terms of toxicity and event free survival. This study assesses the predictive performance of this busulfan PK model in a new, more diverse pediatric population, including data from patients with different underlying diseases, ethnicities, body weights, ages, and body mass indices, from 5 international pediatric transplant centers.
The previously published (original) busulfan PK model was developed from data of 245 patients (0.1-26 years of age). To externally validate this model, data were collected from another 158 patients (0.1-35 years) who underwent hematopoietic stem cell transplantation in 5 international transplant centers. Observed versus predicted plots, normalized prediction distribution error analysis, refit of the model on the external (n = 158) and combined datasets (n = 403), and subpopulation analyses were evaluated.
The original busulfan PK model was found to be stable and parameter estimates precise. Concentrations predicted by this model were in good agreement with the observed concentrations from the 5 external datasets. Plasma concentrations in patients with different underlying diseases, ethnicities, body weights, ages, and body mass indices were adequately predicted.
Our pediatric busulfan PK model has been externally validated. This model predicts busulfan concentrations in pediatric and young adult patients ranging between 3 and 86 kg without bias and with good precision, regardless of transplant center, underlying disease, ethnicity, body weight age, or body mass index. This busulfan PK model forms the basis for individualized busulfan dosing.
最近，开发了一种儿童药代动力学（PK）模型来解释儿童中广泛存在的白消安 PK 变异性，因为这种变异性已知会影响造血干细胞移植的结果，包括毒性和无事件生存。本研究评估了该白消安 PK 模型在新的、更多样化的儿科人群中的预测性能，包括来自 5 个国际儿科移植中心的具有不同基础疾病、种族、体重、年龄和身体质量指数的患者的数据。
之前发表的（原始）白消安 PK 模型是从 245 名患者（0.1-26 岁）的数据中开发的。为了对外验证该模型，从另外 158 名（0.1-35 岁）接受造血干细胞移植的患者中收集数据，这些患者来自 5 个国际移植中心。评估了观察到的与预测到的图、归一化预测分布误差分析、对外部（n = 158）和联合数据集（n = 403）的模型重新拟合以及亚组分析。
原始白消安 PK 模型被发现是稳定的，参数估计是精确的。该模型预测的浓度与来自 5 个外部数据集的观察到的浓度吻合良好。具有不同基础疾病、种族、体重、年龄和身体质量指数的患者的血浆浓度得到了充分的预测。
我们的儿科白消安 PK 模型已经过外部验证。该模型可预测 3 至 86 公斤的儿科和年轻成年患者的白消安浓度，没有偏差且具有良好的精度，而与移植中心、基础疾病、种族、体重、年龄或身体质量指数无关。该白消安 PK 模型为个体化白消安给药提供了基础。
