Wang Jing, Iyer Suhasini, Fielder Paul J, Davis John D, Deng Rong
Global DMPK, Takeda California, San Diego, CA, USA.
Tesaro, Inc., Waltham, MA, USA.
Biopharm Drug Dispos. 2016 Mar;37(2):51-65. doi: 10.1002/bdd.1952. Epub 2015 May 15.
Currently, more than 350 monoclonal antibodies (mAbs) and mAb derivatives are under development as therapeutics. The prediction of mAb pharmacokinetics (PK)/pharmacodynamics (PD) plays a key role in starting dose selection for first-in-human (FIH) studies. This article presents a brief overview of the biology and mechanisms of absorption, distribution, metabolism and excretion (ADME) for mAbs. In addition, a detailed review of mAb human PK/PD prediction from nonclinical data is provided, including allometry for mAbs with linear or nonlinear PK, species-invariant time method, physiologically based PK (PBPK) modeling and target-mediated drug disposition (TMDD) model, bioavailability projection and immunogenicity impact on PK prediction. Finally, from an industry perspective a decision tree of mAb human PK projection is proposed to facilitate drug development.
目前，有超过350种单克隆抗体（mAb）和mAb衍生物正作为治疗药物进行研发。单克隆抗体药代动力学（PK）/药效学（PD）的预测在首次人体（FIH）研究的起始剂量选择中起着关键作用。本文简要概述了单克隆抗体的生物学特性以及吸收、分布、代谢和排泄（ADME）机制。此外，还详细综述了从非临床数据预测单克隆抗体人体PK/PD的方法，包括具有线性或非线性PK的单克隆抗体的异速生长法、物种不变时间法、基于生理学的药代动力学（PBPK）建模和靶介导药物处置（TMDD）模型、生物利用度预测以及免疫原性对PK预测的影响。最后，从行业角度提出了一个单克隆抗体人体PK预测的决策树，以促进药物研发。
