Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects.
Improving Pediatric Protein Binding Estimates: An Evaluation of α1-Acid Glycoprotein Maturation in Healthy and Infected Subjects.
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DOI：
10.1007/s40262-017-0576-7
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发表时间：
2018-05
影响因子：
4.5
通讯作者：
Edginton AN
中科院分区：
文献类型：
--
作者：
Maharaj AR;Gonzalez D;Cohen-Wolkowiez M;Hornik CP;Edginton AN
在儿童和成人之间观察到的血浆蛋白浓度的差异可以改变血浆中异生物质结合的程度，导致不同的暴露模式。本研究用于定量健康和感染受试者中α-1-酸性糖蛋白（AAG）的个体发生。在26篇不同的出版物中汇编了健康受试者的AAG相关数据。对于诊断或疑似感染的受试者，从3项临床研究中获得的214例个体中获得AAG浓度。该分析评价了使用线性、幂、指数、对数线性和S形Emax模型描述AAG的个体发育。使用平均倍数误差（AFE）和绝对平均倍数误差（AAFE）分别作为偏倚和精密度的指标，评价了推导出的个体发育方程用于估计儿科未结合分数（fu）的效用。使用以前提出的线性方程得出的傅估计值进行比较也成立。在健康和感染的受试者中，S形Emax模型提供了AAG个体发育的相对最佳描述。尽管感染受试者的中位AAG浓度是健康受试者中观察到的浓度的2倍以上，但当浓度向成人水平标准化时，观察到类似的个体发育模式。对于儿科fu的估计，与之前的方程（AFE 0.74; AAFE 1.45）相比，从这项工作中推导出的AAG个体发育方程（AFE 0.99; AAFE 1.24）提供了上级预测性能。目前的研究描绘了一个熟练的模式，估计蛋白结合在儿科，因此，将有助于减少与儿科药代动力学预测的不确定性。
Differences in plasma protein concentrations observed between children and adults can alter the extent of xenobiotic binding in plasma, resulting in divergent patterns of exposure. This study serves to quantify the ontogeny of α-1-acid glycoprotein (AAG) in both healthy and infected subjects. Data pertaining to AAG from healthy subjects were compiled over 26 different publications. For subjects diagnosed or suspected of infection, AAG concentrations were obtained from 214 individuals acquired over 3 clinical investigations. The analysis evaluated use of linear, power, exponential, log-linear, and sigmoid Emax models to describe the ontogeny of AAG. Utility of the derived ontogeny equation for estimation of pediatric fraction unbound (fu) was evaluated using average-fold error (AFE) and absolute average-fold error (AAFE) as measures of bias and precision, respectively. A comparison to fu estimates derived using a previously proposed linear equation was also instituted. The sigmoid Emax model provided the comparatively best depiction of AAG ontogeny in both healthy and infected subjects. Despite median AAG concentrations in infected subjects being more than 2-fold greater than those observed in healthy subjects, a similar ontogeny pattern was observed when concentrations were normalized toward adult levels. For estimation of pediatric fu, the AAG ontogeny equation derived from this work (AFE 0.99; AAFE 1.24) provided a superior predictive performance in comparison to the previous equation (AFE 0.74; AAFE 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.
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影响因子：
6.7
作者：
Ballou, SP;Lozanski, GB;Kushner, I
通讯作者：
Kushner, I
影响因子：
2.9
作者：
Johnson, JA;Livingston, TN
通讯作者：
Livingston, TN
影响因子：
10.4
作者：
Edginton AN;Ritter L
通讯作者：
Ritter L
影响因子：
2.9
作者：
KISHINO, S;NOMURA, A;MIYAZAKI, K
通讯作者：
MIYAZAKI, K
DOI：
10.1111/j.1365-2125.1984.tb02567.x
发表时间：
1984-01-01
影响因子：
3.4
作者：
BENEDEK, IH;BLOUIN, RA;MCNAMARA, PJ
通讯作者：
MCNAMARA, PJ