物种间转化细胞单克隆抗体（mAbs）药代动力学（PK）在目标介导药物分布（TMDD）存在时尤为具有挑战性。将TMDD纳入生理基于PK（PBPK）建模是最新的，需要巩固并广泛化，以提供更好的mAbs在临床前和临床开发步骤中关于物种间转化的预测。本研究的目标是使用开源软件（PK-Sim®和Mobi®）开发一种通用的PBPK转化方法，用于mAbs。基于非人灵长类动物（NHP），健康志愿者（HV）和癌症患者的数据，使用分支杠杆创建模型。首先，使用PK-Sim®建立了bevacizumab PK的线性部分（主要是FcRn介导的），随后使用MoBi®开发了目标介导部分。首先，将模型应用于NHP，用于HV的先验PK预测。然后，使用在HV中得到的修正模型进行癌症患者的先验预测。先验预测在浓度-时间曲线下的面积（AUC）和最大浓度（Cmax）均在2倍预测误差范围内，并且所有预测浓度均在2倍平均倍数误差（AFE）和平均绝对倍数误差（AAFE）范围内。敏感性分析表明，FcRn介导的分布和消除过程在所有mAb浓度水平上都必须考虑，而mAb浓度越低，目标介导的消除越显著。该项目是将OSP Suite中的完整PBPK转化方法概括到mAbs的模型指导药物开发（MIDD）中的第一步。

Interspecies translation of monoclonal antibodies (mAbs) pharmacokinetics (PK) in presence of target-mediated drug disposition (TMDD) is particularly challenging. Incorporation of TMDD in physiologically based PK (PBPK) modeling is recent and needs to be consolidated and generalized to provide better prediction of TMDD regarding inter-species translation during preclinical and clinical development steps of mAbs. The objective of this study was to develop a generic PBPK translational approach for mAbs using the open-source software (PK-Sim® and Mobi®). The translation of bevacizumab based on data in non-human primates (NHP), healthy volunteers (HV), and cancer patients was used as a case example for model demonstration purpose. A PBPK model for bevacizumab concentration-time data was developed using data from literature and the Open Systems Pharmacology (OSP) Suite version 10. PK-sim® was used to build the linear part of bevacizumab PK (mainly FcRn-mediated), whereas MoBi® was used to develop the target-mediated part. The model was first developed for NHP and used for a priori PK prediction in HV. Then, the refined model obtained in HV was used for a priori prediction in cancer patients. A priori predictions were within 2-fold prediction error (predicted/observed) for both area under the concentration-time curve (AUC) and maximum concentration (Cmax) and all the predicted concentrations were within 2-fold average fold error (AFE) and average absolute fold error (AAFE). Sensitivity analysis showed that FcRn-mediated distribution and elimination processes must be accounted for at all mAb concentration levels, whereas the lower the mAb concentration, the more significant the target-mediated elimination. This project is the first step to generalize the full PBPK translational approach in Model-Informed Drug Development (MIDD) of mAbs using OSP Suite.