Robarge Jason D, Budge Kevin M, Her Lucy, Patterson Andrea M, Brown-Augsburger Patricia
Eli Lilly and Company, Lilly Corporate Center Indianapolis, Indianapolis, IN 46285, USA.
Antibodies (Basel). 2024 Dec 24;14(1):2. doi: 10.3390/antib14010002.
The prediction of human clearance (CL) and subcutaneous (SC) bioavailability is a critical aspect of monoclonal antibody (mAb) selection for clinical development. While monkeys are a well-accepted model for predicting human CL, other preclinical species have been less-thoroughly explored. Unlike CL, predicting the bioavailability of SC administered mAbs in humans remains challenging as contributing factors are not well understood, and preclinical models have not been systematically evaluated.
Non-clinical and clinical pharmacokinetic (PK) parameters were mined from public and internal sources for rats, cynomolgus monkeys, and humans. Intravenous (IV) and SC PK was determined in Sprague Dawley rats for fourteen mAbs without existing PK data. Together, we obtained cross-species data for 25 mAbs to evaluate CL and SC bioavailability relationships among rats, monkeys, and humans.
Rat and monkey CL significantly correlated with human CL and supported the use of species-specific exponents for body-weight-based allometric scaling. Notably, rat SC bioavailability significantly correlated with human SC bioavailability, while monkey SC bioavailability did not. Bioavailability also correlated with clearance.
The rat model enables an early assessment of mAb PK properties, allowing discrimination among molecules in the discovery pipeline and prediction of human PK. Importantly, rat SC bioavailability significantly correlated with human SC bioavailability, which has not been observed with other species. Rats are cost-effective and efficient relative to monkeys and provide a valuable tool for pharmacokinetic predictions in therapeutic antibody discovery.
预测人体清除率（CL）和皮下（SC）生物利用度是单克隆抗体（mAb）临床开发选择中的关键环节。虽然猴子是预测人体CL的公认模型，但对其他临床前物种的研究却不够深入。与CL不同，预测皮下给药的mAb在人体中的生物利用度仍然具有挑战性，因为相关影响因素尚未完全明确，且临床前模型也未得到系统评估。
从公开和内部来源挖掘大鼠、食蟹猴和人类的非临床和临床药代动力学（PK）参数。在Sprague Dawley大鼠中测定了14种无现有PK数据的mAb的静脉注射（IV）和皮下PK。我们总共获得了25种mAb的跨物种数据，以评估大鼠、猴子和人类之间的CL和SC生物利用度关系。
大鼠和猴子的CL与人体CL显著相关，并支持使用基于体重的异速生长比例缩放的物种特异性指数。值得注意的是，大鼠的SC生物利用度与人体SC生物利用度显著相关，而猴子的SC生物利用度则不然。生物利用度也与清除率相关。
大鼠模型能够对mAb的PK特性进行早期评估，有助于在发现阶段区分不同分子并预测人体PK。重要的是，大鼠的SC生物利用度与人体SC生物利用度显著相关，这在其他物种中尚未观察到。相对于猴子，大鼠具有成本效益且效率高，为治疗性抗体发现中的药代动力学预测提供了有价值的工具。
