Quantitative Clinical Pharmacology, Daiichi Sankyo, Inc., 211 Mt. Airy Road, Basking Ridge, New Jersey, 07920, USA.
AAPS J. 2023 May 25;25(4):53. doi: 10.1208/s12248-023-00818-1.
The prediction of bioavailability is one of the major barriers in the clinical translation of subcutaneously (SC) administered therapeutic monoclonal antibodies (mAbs) due to the lack of reliable in vitro and preclinical in vivo predictive models. Recently, multiple linear regression (MLR) models were developed to predict human SC bioavailability of mAbs using human linear clearance (CL) and isoelectric point (pI) of the whole antibody or Fv regions as independent variables. Unfortunately, these models cannot be applied to mAbs at the preclinical development stage because human CLs of these mAbs are unknown. In this study, we predicted human SC bioavailability of mAbs using preclinical data only by two approaches. In the first approach, allometric scaling was used to predict human linear CL from non-human primate (NHP) linear CL. The predicted human CL and the pI of the whole antibody or Fv regions were then incorporated into two previously published MLR models to predict the human bioavailability of 61 mAbs. In the second approach, two MLR models were developed using NHP linear CL and the pI of whole antibody or Fv regions of 41 mAbs in a training set. The two models were validated using an independent test dataset containing 20 mAbs. The four MLR models generated 77-85% of predictions within 0.8- to 1.2-fold deviations from observed human bioavailability. Overall, this study demonstrated that human SC bioavailability of mAbs at the preclinical stage could be predicted using NHP CL and pI of mAbs.
预测生物利用度是皮下(SC)给药治疗性单克隆抗体(mAb)临床转化的主要障碍之一,因为缺乏可靠的体外和临床前体内预测模型。最近,已经开发了多种线性回归(MLR)模型,使用人源抗体的线性清除率(CL)和等电点(pI)作为独立变量来预测 mAb 的人体 SC 生物利用度。不幸的是,由于这些 mAb 的人体 CL 未知,这些模型无法应用于临床前开发阶段的 mAb。在这项研究中,我们仅通过两种方法使用临床前数据来预测 mAb 的人体 SC 生物利用度。在第一种方法中,我们使用比例模型从非人灵长类动物(NHP)的线性 CL 预测人体的线性 CL。然后将预测的人体 CL 和整个抗体或 Fv 区域的 pI 纳入两个之前发表的 MLR 模型中,以预测 61 种 mAb 的人体生物利用度。在第二种方法中,使用 41 种 mAb 的 NHP 线性 CL 和整个抗体或 Fv 区域的 pI 建立了两个 MLR 模型。使用包含 20 种 mAb 的独立测试数据集对这两个模型进行验证。四个 MLR 模型生成的预测值有 77%-85%在观察到的人体生物利用度的 0.8 到 1.2 倍偏差内。总体而言,这项研究表明,使用 NHP CL 和 mAb 的 pI 可以预测临床前阶段 mAb 的人体 SC 生物利用度。