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单克隆抗体的线性药代动力学参数在同种内和不同的药理学靶标之间相似:使用群体建模方法在人、食蟹猴和 hFcRn Tg32 转基因小鼠之间进行比较。

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach.

机构信息

a Department of Biomedicine Design , Pfizer Inc. , Cambridge , MA , USA.

b LAP&P , The Netherlands.

出版信息

MAbs. 2018 Jul;10(5):751-764. doi: 10.1080/19420862.2018.1462429. Epub 2018 May 14.

Abstract

The linear pharmacokinetics (PK) of therapeutic monoclonal antibodies (mAbs) can be considered a class property with values that are similar to endogenous IgG. Knowledge of these parameters across species could be used to avoid unnecessary in vivo PK studies and to enable early PK predictions and pharmacokinetic/pharmacodynamic (PK/PD) simulations. In this work, population-pharmacokinetic (popPK) modeling was used to determine a single set of 'typical' popPK parameters describing the linear PK of mAbs in human, cynomolgus monkey and transgenic mice expressing the human neonatal Fc receptor (hFcRn Tg32), using a rich dataset of 27 mAbs. Non-linear PK was excluded from the datasets and a 2-compartment model was applied to describe mAb disposition. Typical human popPK estimates compared well with data from comparator mAbs with linear PK in the clinic. Outliers with higher than typical clearance were found to have non-specific interactions in an affinity-capture self-interaction nanoparticle spectroscopy assay, offering a potential tool to screen out these mAbs at an early stage. Translational strategies were investigated for prediction of human linear PK of mAbs, including use of typical human popPK parameters and allometric exponents from cynomolgus monkey and Tg32 mouse. Each method gave good prediction of human PK with parameters predicted within 2-fold. These strategies offer alternative options to the use of cynomolgus monkeys for human PK predictions of linear mAbs, based on in silico methods (typical human popPK parameters) or using a rodent species (Tg32 mouse), and call into question the value of completing extensive in vivo preclinical PK to inform linear mAb PK.

摘要

治疗性单克隆抗体(mAbs)的线性药代动力学(PK)可被视为一类特性,其值与内源性 IgG 相似。了解这些参数在不同物种间的差异,可用于避免不必要的体内 PK 研究,并实现早期 PK 预测和药代动力学/药效学(PK/PD)模拟。在这项工作中,使用群体药代动力学(popPK)建模来确定一组“典型”popPK 参数,用于描述人、食蟹猴和表达人新生 Fc 受体(hFcRn Tg32)的转基因小鼠中 mAbs 的线性 PK,使用 27 种 mAbs 的丰富数据集。从数据集排除了非线性 PK,并应用 2 隔室模型来描述 mAb 处置。典型的人体 popPK 估计值与具有线性 PK 的临床对照 mAbs 的数据吻合良好。发现具有高于典型清除率的离群值在亲和力捕获自相互作用纳米颗粒光谱测定法中具有非特异性相互作用,这为早期筛选出这些 mAb 提供了一种潜在工具。研究了用于预测 mAbs 人线性 PK 的转化策略,包括使用典型的人体 popPK 参数和食蟹猴和 Tg32 小鼠的体表面积指数。每种方法都能很好地预测人体 PK,预测的参数在 2 倍以内。这些策略为基于计算方法(典型人体 popPK 参数)或使用啮齿动物物种(Tg32 小鼠)的线性 mAbs 人体 PK 预测提供了替代使用食蟹猴的选择,并对完成广泛的体内临床前 PK 以告知线性 mAb PK 的价值提出了质疑。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b75f/6150614/deb28b4404e5/kmab-10-05-1462429-g001.jpg

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