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
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
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DOI：
10.1080/19420862.2018.1462429
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发表时间：
2018-01-01
期刊：
影响因子：
5.3
通讯作者：
Berkhout, Jan
中科院分区：
文献类型：
--
作者：
Betts, Alison;Keunecke, Anne;Berkhout, Jan
治疗性单克隆抗体（mAb）的线性药代动力学（PK）可被视为具有与内源性IgG相似值的类属性。跨物种的这些参数的知识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27种mAb的丰富数据集，使用群体药代动力学（popPK）建模来确定描述mAb在人、食蟹猴和表达人新生儿Fc受体（hFcRn Tg 32）的转基因小鼠中的线性PK的单组典型“popPK”参数。从数据集中排除非线性PK，并采用2室模型描述mAb分布。典型的人popPK估计值与临床中具有线性PK的对照mAb的数据比较良好。发现具有高于典型清除率的离群值在亲和捕获自相互作用纳米颗粒光谱测定中具有非特异性相互作用，这提供了在早期阶段筛选出这些mAb的潜在工具。研究了预测mAb的人线性PK的翻译策略，包括使用食蟹猴和Tg 32小鼠的典型人popPK参数和异速生长指数。每种方法均能很好地预测人体PK，预测参数在2倍以内。这些策略为使用食蟹猴进行线性mAb的人PK预测提供了替代选择，基于计算机模拟方法（典型的人popPK参数）或使用啮齿动物种属（Tg 32小鼠），并质疑完成广泛的体内临床前PK以告知线性mAb PK的价值。
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 27mAbs. 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.