Characterizing the Developmental Trajectory of Sirolimus Clearance in Neonates and Infants.
Characterizing the Developmental Trajectory of Sirolimus Clearance in Neonates and Infants.
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DOI：
10.1002/psp4.12096
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发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
Vinks AA
中科院分区：
文献类型：
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作者：
Emoto C;Fukuda T;Mizuno T;Schniedewind B;Christians U;Adams DM;Vinks AA
西罗莫司越来越多地用于新生儿和婴儿，但西罗莫司处置的年龄依赖性变化的机制基础尚未完全解决。为了表征年龄依赖性变化，收集个体年轻儿科患者的系列西罗莫司清除率（CL）估计值，并通过群体建模分析进行分析。此外，还研究了西罗莫司代谢产物的形成，以进一步证实CYP3A活性的相应年龄依赖性变化。通过S形Emax模型很好地描述了异速生长尺寸归一化西罗莫司CL估计值随时间的增加模式与年龄。在4年的研究期间，在每例患者中也观察到这种年龄依赖性增加。CYP3A依赖性西罗莫司代谢产物的形成以相似的方式发生变化。本研究清楚地表明，新生儿和婴儿中西罗莫司CL随时间迅速增加，表明发育变化。这种发育模式可以通过CYP3A代谢活性的平行增加来解释。
Sirolimus is increasingly being used in neonates and infants, but the mechanistic basis of age‐dependent changes in sirolimus disposition has not been fully addressed yet. In order to characterize the age‐dependent changes, serial sirolimus clearance (CL) estimates in individual young pediatric patients were collected and analyzed by population modeling analysis. In addition, sirolimus metabolite formation was also investigated to further substantiate the corresponding age‐dependent change in CYP3A activity. The increasing pattern over time of allometrically size‐normalized sirolimus CL estimates vs. age was well described by a sigmoidal Emax model. This age‐dependent increase was also observed within each individual patient over a 4‐year study period. CYP3A‐dependent sirolimus metabolite formation changed in a similar fashion. This study clearly demonstrates the rapid increase of sirolimus CL over time in neonates and infants, indicating the developmental change. This developmental pattern can be explained by a parallel increase in CYP3A metabolic activity.