Development of a Pediatric Physiologically Based Pharmacokinetic Model for Sirolimus: Applying Principles of Growth and Maturation in Neonates and Infants.
Development of a Pediatric Physiologically Based Pharmacokinetic Model for Sirolimus: Applying Principles of Growth and Maturation in Neonates and Infants.
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DOI：
10.1002/psp4.17
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发表时间：
2015-02
影响因子：
3.5
通讯作者：
Vinks, A A
中科院分区：
文献类型：
--
作者：
Emoto, C;Fukuda, T;Johnson, T N;Adams, D M;Vinks, A A
本研究描述了西罗莫司清除率在一组非常年轻的血管异常儿科患者中的成熟情况。在1个月至2岁的患者中，通过Emax模型描述了异速生长比例体内清除率与年龄之间的关系。与观察到的增加一致，使用儿科肝微粒体进行的西罗莫司体外固有清除率显示出相似的年龄依赖性增加。在2岁以上的儿童中，异速生长比例的西罗莫司清除率未显示进一步成熟。采用西罗莫司生理药代动力学模型（包括CYP 3A 4/5/7和CYP 2C 8成熟特征）模拟的清除率估计值与观察到的体内清除率值非常一致。此外，基于生理学的药代动力学模型模拟的西罗莫司药代动力学曲线很好地预测了实际观察结果。这些结果证明了基于生理学的药代动力学建模方法用于预测西罗莫司代谢活性的发育轨迹及其对新生儿和婴儿全身清除率的影响的实用性。
This study describes the maturation of sirolimus clearance in a cohort of very young pediatric patients with vascular anomalies. The relationship between allometrically scaled in vivo clearance and age was described by the Emax model in patients aged 1 month to 2 years. Consistent with the observed increase, in vitro intrinsic clearance of sirolimus using pediatric liver microsomes showed a similar age-dependent increase. In children older than 2 years, allometrically scaled sirolimus clearance did not show further maturation. Simulated clearance estimates with a sirolimus physiologically based pharmacokinetic model that included CYP3A4/5/7 and CYP2C8 maturation profiles were in close agreement with observed in vivo clearance values. In addition, physiologically based pharmacokinetic model-simulated sirolimus pharmacokinetic profiles predicted the actual observations well. These results demonstrate the utility of a physiologically based pharmacokinetic modeling approach for the prediction of the developmental trajectory of sirolimus metabolic activity and its effects on total body clearance in neonates and infants.