Duan Peng, Fisher Jeffrey W, Yoshida Kenta, Zhang Lei, Burckart Gilbert J, Wang Jian
Office of New Drug Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD, 20993, USA.
National Center for Toxicological Research, US Food and Drug Administration, 3900 NCTR Rd, Jefferson, AR, 72079, USA.
Clin Pharmacokinet. 2017 Apr;56(4):383-394. doi: 10.1007/s40262-016-0445-9.
Modeling and simulation approaches are increasingly being utilized in pediatric drug development. Physiologically based pharmacokinetic (PBPK) modeling offers an enhanced ability to predict age-related changes in pharmacokinetics in the pediatric population.
In the current study, adult PBPK models were developed for the renally excreted drugs linezolid and emtricitabine. PBPK models were then utilized to predict pharmacokinetics in pediatric patients for various age groups from the oldest to the youngest patients in a stepwise approach.
Pharmacokinetic predictions for these two drugs in the pediatric population, including infants and neonates, were within a twofold range of clinical observations. Based on this study, linezolid and emtricitabine pediatric PBPK models incorporating the ontogeny in renal maturation describe the pharmacokinetic differences between adult and pediatric populations, even though the contribution of renal clearance to the total clearance of two drugs was very different (30 % for linezolid vs. 86 % for emtricitabine).
These results suggest that PBPK modeling may provide one option to help predict the pharmacokinetics of renally excreted drugs in neonates and infants.
建模与模拟方法在儿科药物研发中越来越多地被使用。基于生理的药代动力学（PBPK）建模在预测儿科人群药代动力学的年龄相关变化方面具有更强的能力。
在本研究中，为经肾脏排泄的药物利奈唑胺和恩曲他滨建立了成人PBPK模型。然后利用PBPK模型，以逐步的方式预测从年龄最大到最小的各个年龄组儿科患者的药代动力学。
这两种药物在儿科人群（包括婴儿和新生儿）中的药代动力学预测值在临床观察值的两倍范围内。基于本研究，纳入肾脏成熟个体发育的利奈唑胺和恩曲他滨儿科PBPK模型描述了成人和儿科人群之间的药代动力学差异，尽管肾脏清除率对两种药物总清除率的贡献差异很大（利奈唑胺为30%，恩曲他滨为86%）。
这些结果表明，PBPK建模可能为帮助预测新生儿和婴儿经肾脏排泄药物的药代动力学提供一种选择。
