Leiden/Amsterdam Center for Drug Research, Division of Pharmacology, Leiden University, Leiden, The Netherlands.
Clin Pharmacol Ther. 2010 Mar;87(3):294-302. doi: 10.1038/clpt.2009.234. Epub 2010 Jan 27.
The establishment of a rationale for determining dosing regimens in pediatric patients remains a challenge in drug development. In this investigation, we explored several methodologies to support bridging studies and evaluated the best descriptor of developmental changes that can be used as a covariate for dose adjustment in children. The proposed approach is illustrated for the antiviral drug abacavir. Using data from six pharmacokinetic studies in adults and one study in children, a model-based analysis was applied in order to characterize differences in parameter distributions and their implications for systemic exposure to abacavir. Simulations were subsequently performed to define the appropriate dosing regimen in children. Although body weight was identified as a covariate for clearance and volume, dosing recommendations calculated on the basis of mg/kg cannot be linearly applied across all weight ranges. Our analysis shows the consequences of empirical dose adjustment and the importance of priors from historical data to support dose selection in children.
在药物开发中，确定儿科患者给药方案的理论基础仍然是一个挑战。在这项研究中，我们探索了几种方法来支持桥接研究，并评估了可作为儿童剂量调整的协变量的发育变化的最佳描述符。所提出的方法以抗病毒药物阿巴卡韦为例进行了说明。使用来自成人的六项药代动力学研究和一项儿童研究的数据，应用基于模型的分析方法来描述参数分布的差异及其对阿巴卡韦全身暴露的影响。随后进行了模拟，以确定儿童的适当给药方案。虽然体重被确定为清除率和体积的协变量，但根据 mg/kg 计算的给药建议不能在所有体重范围内线性应用。我们的分析表明了经验性剂量调整的后果，以及来自历史数据的先验信息对支持儿童剂量选择的重要性。
