School of Pharmacy, University of Waterloo, 10A Victoria St. S, Kitchener, ON, Canada.
Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Clin Pharmacokinet. 2018 May;57(5):577-589. doi: 10.1007/s40262-017-0576-7.
Differences in plasma protein levels observed between children and adults can alter the extent of xenobiotic binding in plasma, resulting in divergent patterns of exposure.
This study aims to quantify the ontogeny of α1-acid glycoprotein in both healthy and infected subjects.
Data pertaining to α1-acid glycoprotein from healthy subjects were compiled over 26 different publications. For subjects diagnosed or suspected of infection, α1-acid glycoprotein levels were obtained from 214 individuals acquired over three clinical investigations. The analysis evaluated the use of linear, power, exponential, log-linear, and sigmoid E models to describe the ontogeny of α1-acid glycoprotein. Utility of the derived ontogeny equation for estimation of pediatric fraction unbound was evaluated using average-fold error and absolute average-fold error as measures of bias and precision, respectively. A comparison to fraction unbound estimates derived using a previously proposed linear equation was also instituted.
The sigmoid E model provided the comparatively best depiction of α1-acid glycoprotein ontogeny in both healthy and infected subjects. Despite median α1-acid glycoprotein levels in infected subjects being more than two-fold greater than those observed in healthy subjects, a similar ontogeny pattern was observed when levels were normalized toward adult levels. For estimation of pediatric fraction unbound, the α1-acid glycoprotein ontogeny equation derived from this work (average fold error 0.99; absolute average fold error 1.24) provided a superior predictive performance in comparison to the previous equation (average fold error 0.74; absolute average fold error 1.45).
The current investigation depicts a proficient modality for estimation of protein binding in pediatrics and will, therefore, aid in reducing uncertainty associated with pediatric pharmacokinetic predictions.
儿童和成人之间血浆蛋白水平的差异会改变血浆中外源物质的结合程度，从而导致暴露模式的不同。
本研究旨在定量研究健康和感染受试者α1-酸性糖蛋白的发育情况。
从 26 篇不同的文献中汇总了有关健康受试者α1-酸性糖蛋白的数据。对于被诊断或疑似感染的患者，从 3 项临床研究中获得了 214 名患者的α1-酸性糖蛋白水平。该分析评估了使用线性、幂、指数、对数线性和 sigmoid E 模型来描述α1-酸性糖蛋白的发育情况。使用平均倍误差和绝对平均倍误差分别作为偏差和精度的度量标准，评估从衍生的发育方程中估算儿科游离分数的实用性。还进行了与使用先前提出的线性方程得出的游离分数估计值的比较。
在健康和感染受试者中，sigmoid E 模型对α1-酸性糖蛋白发育的描述相对较好。尽管感染受试者的α1-酸性糖蛋白中位数水平是健康受试者的两倍多，但当水平归一化到成人水平时，观察到了相似的发育模式。对于儿科游离分数的估算，从这项工作中得出的α1-酸性糖蛋白发育方程（平均倍误差 0.99；绝对平均倍误差 1.24）在预测性能方面优于以前的方程（平均倍误差 0.74；绝对平均倍误差 1.45）。
本研究描述了一种估计儿科蛋白质结合的有效方法，因此将有助于减少与儿科药代动力学预测相关的不确定性。
