Office of Tissue & Advanced Therapies (OTAT), Center for Biologics Evaluation and Research, Food & Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993-0002, USA.
Office of Biostatistics & Epidemiology, Center for Biologics Evaluation and Research, Food & Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD, 20993-0002, USA.
Regul Toxicol Pharmacol. 2018 Aug;97:57-62. doi: 10.1016/j.yrtph.2018.06.004. Epub 2018 Jun 13.
The objectives of this study were to develop and evaluate allometric methods for predicting tissue-to-plasma partition coefficients (Kp) in mice from experimentally determined in-vivo volume of distribution at steady state (Vss) for monoclonal antibodies (mAbs). The Vss was allometrically predicted (using a fixed exponent 1.0 or 0.9) in a given tissue of the mice. The Kp was predicted using Vss and tissue specific physiological parameters. In total, Kp values were predicted for 20 mAbs, 121 tissues, and 665 tissue concentrations. The predicted Kp values and tissue concentrations were compared with the experimental results as well as an empirically predicted antibody biodistribution coefficient (ABC). Comparison of the predicted Kp values by the two proposed methods with experimentally determined Kp values indicated that 64-75% of the predicted Kp values were within two-fold prediction error. For 665 tissue concentrations, 63%, 74%, and 48% tissue concentration ratio were within 0.5-2 fold prediction error by exponent 1.0, exponent 0.9, and ABC, respectively. The proposed allometric methods are better than ABC method for the prediction of tissue Kp values and tissue concentrations. The proposed methods can reasonably predict tissue concentrations of mAbs using plasma concentration gathered at early stage of biologics development.
本研究旨在开发和评估从单克隆抗体（mAb）体内稳态分布容积（Vss）的实验测定值来预测小鼠组织-血浆分配系数（Kp）的比例法。使用固定指数 1.0 或 0.9 对小鼠的特定组织进行 Vss 比例预测。Kp 使用 Vss 和组织特异性生理参数进行预测。总共预测了 20 种 mAb、121 种组织和 665 种组织浓度的 Kp 值。预测的 Kp 值和组织浓度与实验结果以及经验预测的抗体生物分布系数（ABC）进行了比较。用两种提出的方法预测的 Kp 值与实验测定的 Kp 值进行比较表明，64-75%的预测 Kp 值在两倍预测误差范围内。对于 665 种组织浓度，指数 1.0、指数 0.9 和 ABC 分别有 63%、74%和 48%的组织浓度比在 0.5-2 倍预测误差范围内。与 ABC 方法相比，比例法更适合预测组织 Kp 值和组织浓度。这些方法可以使用在生物制品开发早期获得的血浆浓度合理地预测 mAb 的组织浓度。
