以抗白细胞介素-33 受体单克隆抗体 GSK3772847 为展示品,采用基于模型的方法,根据静脉注射后的 PK 和总目标测量值预测静脉注射 PK 和游离目标动态。

IF 3.1 3区 医学 Q2 PHARMACOLOGY & PHARMACY
Jan Berkhout, Dave Fairman, Martijn van Noort, Tamara J van Steeg
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引用次数: 0

摘要

通过 TMDD 模型对药物动力学(PK)和靶点结合进行综合建模,可以为了解单克隆抗体(mAbs)的预期药效学(PD)效应提供有价值的见解。人体 PK 和 mAbs 靶点结合的最佳表征需要静脉注射(IV)后获得的数据,这些数据可与皮下注射(SC)数据相结合以进一步表征。在群体 TMDD 模型中整合游离靶标和/或总靶标测量值,就能量化靶标结合,而靶标结合是导致疗效的级联反应的第一步。然而,测定游离靶标浓度的检测方法在分析上极具挑战性,而且在存在 mAb:靶标复合物的情况下,这种检测方法本身就存在偏差,会高估真实浓度。因此,当前研究的目的是评估游离靶标浓度在仅使用 PK 和总靶标观察结果开发的 TMDD 模型中的预测价值。此外,研究的另一个目的是根据现有的 IV 模型和已报道的用于 SC 吸收的 mAb 参数的典型值,证明 SC 数据的预测是可行的。GSK3772847 是一种人免疫球蛋白 G2 sigma 异型 (IgG2f) mAb,它能与白细胞介素-33 受体(IL-33R 或 ST2)的胞外结构域结合并中和 IL-33 介导的 ST2 信号传导,在本研究中被用作 mAb 的模型化合物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
A model-based approach using GSK3772847, an anti-interleukin-33 receptor monoclonal antibody, as a showcase to predict SC administration PK and free target dynamics based on PK and total target measurements after IV administration.

Integrated modeling of the pharmacokinetic (PK) and target binding, by means of a TMDD model, can provide valuable insights into the expected pharmacodynamic (PD) effects of monoclonal antibodies (mAbs). Optimal characterization of the human PK and target binding for mAbs requires data obtained after intravenous (IV) administration which can be combined with subcutaneous (SC) data to further this characterization. Integration of free and/or total target measurements in a population TMDD model will allow quantification of target engagement which is the first step in the cascade leading to efficacy. However, the assays for determination of free target concentrations are analytically challenging and are inherently biased to overpredict the true concentrations in the presence of mAb:target complexes. For that reason, the objective of the current research was to evaluate the predictive value of free target concentrations in a TMDD model developed using PK and total target observations only. Further, a secondary objective was to demonstrate that prediction of SC data is feasible, based on an existing IV model and typical values of mAb parameters reported for SC absorption. GSK3772847, a human immunoglobulin G2 sigma isotype (IgG2f) mAb that binds to the extracellular domain of the interleukin-33 receptor (IL-33R or ST2) and neutralizes IL-33-mediated ST2 signaling, was used as a model compound for mAbs in this study.

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来源期刊
CiteScore
5.00
自引率
11.40%
发文量
146
审稿时长
8 weeks
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