a College of Pharmacy , University of Kentucky , Lexington , USA.
MAbs. 2018 Oct;10(7):1144-1156. doi: 10.1080/19420862.2018.1494479. Epub 2018 Jul 30.
The aim of this study was to investigate neonatal Fc receptor (FcRn) concentration developmental pharmacology in adult and pediatric subjects using minimal physiologically-based pharmacokinetic (mPBPK) modelling. Three types of pharmacokinetic (PK) data for three agents (endogenous/exogenous native IgG, bevacizumab and palivizumab) were used. The adult group contained six subjects with weights from 50 to 100 kg. For pediatric subjects, seven age groups were assumed, with five subjects each having the weight of 95%, 75%, 50%, 25% and 5% percentile of the population. A first evidence-based rating system to evaluate the quality of the source data used to derive pediatric-specific mPBPK model parameter was proposed. A stepwise approach was used to examine the best combination of age/weight effect on the parameters of the mPBPK model in adult and pediatric subjects. IgG synthesis rate (K), extravasation rate (ER) and FcRn were fitted simultaneously to the PK of bevacizumab and native-IgG in both adult and pediatric. All fitting showed good fits based on the graphs and the coefficient of variation of the fitted parameters (< 50%). Estimated weight-normalized K increased while weight-normalized FcRn and ER decreased with increasing age. The age and weight effect on FcRn were successfully estimated from the data. The final mPBPK model developed with native IgG and bevacizumab was able to predict the PK of palivizumab in pediatric subjects. Implementation of the mPBPK model enables us to analyze the relationships of age, weight, FcRn, ER and K in both adult and pediatric subject. This information may benefit the understanding of complex interaction between the FcRn developmental pharmacology and PK parameters, and improve the prediction of the antibody disposition in pediatric subjects.
本研究旨在通过最小生理基于药代动力学(mPBPK)模型研究成人和儿科受试者中新生儿 Fc 受体(FcRn)浓度的发育药代动力学。使用三种药物(内源性/外源性天然 IgG、贝伐珠单抗和帕利珠单抗)的三种类型的药代动力学(PK)数据。成人组包含 6 名体重 50-100kg 的受试者。对于儿科受试者,假设了 7 个年龄组,每个年龄组有 5 名体重为人群 95%、75%、50%、25%和 5%百分位的受试者。提出了第一个基于证据的评分系统,用于评估用于推导儿科特定 mPBPK 模型参数的源数据的质量。采用逐步方法检查成人和儿科受试者中 mPBPK 模型参数的年龄/体重影响的最佳组合。在成人和儿科受试者中,同时对贝伐珠单抗和天然 IgG 的 PK 拟合 IgG 合成率(K)、外渗率(ER)和 FcRn。所有拟合均基于图形和拟合参数的变异系数(<50%)显示出良好的拟合。估计的体重标准化 K 随着年龄的增加而增加,而体重标准化 FcRn 和 ER 随着年龄的增加而降低。从数据中成功估计了 FcRn 的年龄和体重影响。使用天然 IgG 和贝伐珠单抗开发的最终 mPBPK 模型能够预测儿科受试者中帕利珠单抗的 PK。mPBPK 模型的实施使我们能够分析成人和儿科受试者中年龄、体重、FcRn、ER 和 K 之间的关系。这些信息可能有助于理解 FcRn 发育药代动力学和 PK 参数之间的复杂相互作用,并改善对儿科受试者中抗体分布的预测。