A population physiologically-based pharmacokinetic model to characterize antibody disposition in pediatrics and evaluation of the model using infliximab.
A population physiologically-based pharmacokinetic model to characterize antibody disposition in pediatrics and evaluation of the model using infliximab.
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DOI：
10.1111/bcp.14963
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发表时间：
2022-01
影响因子：
3.4
通讯作者：
Shah DK
中科院分区：
文献类型：
--
作者：
Chang HP;Shakhnovich V;Frymoyer A;Funk RS;Becker ML;Park KT;Shah DK
为了更好地预测儿童中抗体的药代动力学（PK），并促进儿科患者中抗体的剂量优化，需要开发整合人体生理参数中个体发育相关变化的系统PK模型。通过在先前发表的平台模型中纳入体重、器官重量、器官血流速率和间质体积的年龄相关变化，开发了一种基于人群的基于生理学的PK（PBPK）模型，用于表征儿科中的抗体PK。该模型进一步用于进行Monte Carlo模拟，以研究英夫利西单抗的清除率与年龄和剂量-暴露量的关系。通过仅估计一个参数和相关的个体间变异性，该模型能够合理地表征两个儿科队列（n = 141，4-19岁）的英夫利西单抗临床PK。模型模拟表明，当接受FDA标记的英夫利西单抗给药方案时，只有50%的儿童达到了预期的谷浓度，这表明需要更高的剂量和/或更频繁的给药才能达到该抗体的目标谷浓度。此处提供的儿科PBPK模型可作为表征儿科患者中抗体PK的框架。该模型也可以应用于其他蛋白质治疗，以推进精准医学范式和优化儿童抗体给药方案。
In order to better predict the pharmacokinetics (PK) of antibodies in children, and to facilitate dose optimization of antibodies in paediatric patients, there is a need to develop systems PK models that integrate ontogeny-related changes in human physiological parameters. A population-based physiological-based PK (PBPK) model to characterize antibody PK in paediatrics has been developed, by incorporating age-related changes in body weight, organ weight, organ blood flow rate and interstitial volumes in a previously published platform model. The model was further used to perform Monte Carlo simulations to investigate clearance vs. age and dose–exposure relationships for infliximab. By estimating only one parameter and associated interindividual variability, the model was able to characterize clinical PK of infliximab from two paediatric cohorts (n = 141, 4–19 years) reasonably well. Model simulations demonstrated that only 50% of children reached desired trough concentrations when receiving FDA-labelled dosing regimen for infliximab, suggesting that higher doses and/or more frequent dosing are needed to achieve target trough concentrations of this antibody. The paediatric PBPK model presented here can serve as a framework to characterize the PK of antibodies in paediatric patients. The model can also be applied to other protein therapeutics to advance precision medicine paradigm and optimize antibody dosing regimens in children.
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