Chugai Pharmaceuticals Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan.
Clin Pharmacokinet. 2021 Jan;60(1):111-120. doi: 10.1007/s40262-020-00917-8.
The subcutaneous injection of therapeutic monoclonal antibodies is increasingly used in the treatment of several diseases because of its convenience. Thus, a simple and accurate method of predicting the pharmacokinetics of monoclonal antibodies after a subcutaneous injection in humans would be a valuable tool for preclinical/clinical development. In this study, we investigated whether the pharmacokinetics of monoclonal antibodies after a subcutaneous injection in humans can be predicted using only pharmacokinetic data after a subcutaneous injection in cynomolgus monkeys.
First, we compared the accuracy of three approaches to predict the apparent clearance (CL/F) and apparent volume of distribution (V/F) for 15 monoclonal antibodies in humans (1) allometric scaling from cynomolgus monkeys; (2) geometric mean of reported values in humans; (3) estimation from a regression line based on CL/F in humans [only V/F]). Then, using the predicted CL/F and V/F, and the geometric mean of reported absorption rate constant of mAbs the plasma concentration-time profiles of 13 monoclonal antibodies after subcutaneous injections in humans were simulated.
In a comparison of approaches, the first approach showed the best prediction accuracy for CL/F with an exponent of 0.9 (100% and 73% prediction accuracy within 2- and 1.5-fold of the observed value),and the third approach was the best for V/F (100% prediction accuracy within 1.5-fold of the observed value). Next, using the first approach for CL/F and the third approach for V/F, we accurately predicted the plasma concentration-time profiles of 13 monoclonal antibodies after subcutaneous injections in humans.
This simple approach can be applied in preclinical and clinical settings to predict the pharmacokinetics of monoclonal antibodies after subcutaneous injections in humans. Further, this approach requires only CL/F after a subcutaneous injection in cynomolgus monkeys, contributing to animal welfare and reducing costs.
由于便利性，治疗性单克隆抗体的皮下注射在多种疾病的治疗中越来越多地被使用。因此，一种简单而准确的方法来预测单克隆抗体在人体皮下注射后的药代动力学，将是临床前/临床开发的有价值的工具。在这项研究中，我们研究了是否可以仅使用恒河猴皮下注射后的药代动力学数据来预测单克隆抗体在人体皮下注射后的药代动力学。
首先，我们比较了三种方法预测 15 种单克隆抗体在人体中的表观清除率（CL/F）和表观分布容积（V/F）的准确性：（1）来自恒河猴的体表面积比例法；（2）人体中报告值的几何平均值；（3）基于人体 CL/F 的回归线估计[仅 V/F]）。然后，使用预测的 CL/F 和 V/F，以及报告的单克隆抗体吸收速率常数的几何平均值，模拟了 13 种单克隆抗体在人体皮下注射后的血浆浓度-时间曲线。
在方法比较中，第一种方法对 CL/F 的预测准确性最好，指数为 0.9（100%和 73%预测准确性在观察值的 2-和 1.5 倍以内），第三种方法对 V/F 最好（100%预测准确性在观察值的 1.5 倍以内）。接下来，使用第一种方法预测 CL/F，第三种方法预测 V/F，我们准确地预测了 13 种单克隆抗体在人体皮下注射后的血浆浓度-时间曲线。
这种简单的方法可应用于临床前和临床环境中，以预测单克隆抗体在人体皮下注射后的药代动力学。此外，这种方法仅需要恒河猴皮下注射后的 CL/F，有助于动物福利和降低成本。
