Department of Biomedical Engineering, University of Southern California, Los Angeles, California, 90089, USA.
Department of Exploratory Medicine and Pharmacology, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana, USA.
AAPS J. 2022 Dec 1;25(1):5. doi: 10.1208/s12248-022-00772-4.
An integrated physiologically based modeling framework is presented for predicting pharmacokinetics and bioavailability of subcutaneously administered monoclonal antibodies in cynomolgus monkeys, based on in silico structure-derived metrics characterizing antibody size, overall charge, local charge, and hydrophobicity. The model accounts for antibody-specific differences in pinocytosis, transcapillary transport, local lymphatic uptake, and pre-systemic degradation at the subcutaneous injection site and reliably predicts the pharmacokinetics of five different wild-type mAbs and their Fc variants following intravenous and subcutaneous administration. Significant associations were found between subcutaneous injection site degradation rate and the antibody's local positive charge of its complementarity-determining region (R = 0.56, p = 0.0012), antibody pinocytosis rate and its overall positive charge (R = 0.59, p = 0.00063), and antibody paracellular transport and its overall charge together with hydrophobicity (R = 0.63, p = 0.00096). Based on these results, population simulations were performed to predict the relationship between bioavailability and antibody local positive charge. In addition, model simulations were conducted to calculate the relative contribution of absorption pathways (lymphatic and blood), pre-systemic degradation pathways (interstitial and lysosomal), and the influence of injection site lymph flow on antibody bioavailability and pharmacokinetics. The proposed physiologically based modeling framework integrates fundamental mechanisms governing antibody subcutaneous absorption and disposition, with structured-based physiochemical properties, to predict antibody bioavailability and pharmacokinetics in vivo.
本文提出了一种整合的生理基础建模框架，用于预测皮下给予食蟹猴单克隆抗体的药代动力学和生物利用度，该模型基于计算结构衍生的指标来描述抗体的大小、整体电荷、局部电荷和疏水性。该模型考虑了抗体在皮下注射部位的内在差异，如胞饮作用、跨毛细血管转运、局部淋巴摄取和系统性前降解，并可靠地预测了五种不同野生型 mAb 及其 Fc 变体静脉内和皮下给药后的药代动力学。在皮下注射部位降解率与抗体互补决定区的局部正电荷之间（R=0.56，p=0.0012）、抗体胞饮率与其整体正电荷之间（R=0.59，p=0.00063），以及抗体的旁细胞转运与其整体电荷和疏水性之间（R=0.63，p=0.00096），发现了显著的相关性。基于这些结果，进行了群体模拟，以预测生物利用度与抗体局部正电荷之间的关系。此外，还进行了模型模拟，以计算吸收途径（淋巴和血液）、系统性前降解途径（间质和溶酶体）的相对贡献，以及注射部位淋巴流量对抗体生物利用度和药代动力学的影响。所提出的生理基础建模框架将控制抗体皮下吸收和处置的基本机制与基于结构的物理化学性质相结合，以预测体内抗体的生物利用度和药代动力学。
