Li Linzhong, Gardner Iain, Dostalek Miroslav, Jamei Masoud
Simcyp Limited, A Certara Company, Blades Enterprise Centre, John Street, Sheffield, S2 4SU, UK,
AAPS J. 2014 Sep;16(5):1097-109. doi: 10.1208/s12248-014-9640-5. Epub 2014 Jul 9.
Compared to small chemical molecules, monoclonal antibodies and Fc-containing derivatives (mAbs) have unique pharmacokinetic behaviour characterised by relatively poor cellular permeability, minimal renal filtration, binding to FcRn, target-mediated drug disposition, and disposition via lymph. A minimal physiologically based pharmacokinetic (PBPK) model to describe the pharmacokinetics of mAbs in humans was developed. Within the model, the body is divided into three physiological compartments; plasma, a single tissue compartment and lymph. The tissue compartment is further sub-divided into vascular, endothelial and interstitial spaces. The model simultaneously describes the levels of endogenous IgG and exogenous mAbs in each compartment and sub-compartment and, in particular, considers the competition of these two species for FcRn binding in the endothelial space. A Monte-Carlo sampling approach is used to simulate the concentrations of endogenous IgG and mAb in a human population. Existing targeted-mediated drug disposition (TMDD) models are coupled with the minimal PBPK model to provide a general platform for simulating the pharmacokinetics of therapeutic antibodies using primarily pre-clinical data inputs. The feasibility of utilising pre-clinical data to parameterise the model and to simulate the pharmacokinetics of adalimumab and an anti-ALK1 antibody (PF-03446962) in a population of individuals was investigated and results were compared to published clinical data.
与小分子化学物质相比，单克隆抗体和含Fc的衍生物（单克隆抗体）具有独特的药代动力学行为，其特征在于细胞通透性相对较差、肾滤过极少、与FcRn结合、靶点介导的药物处置以及通过淋巴进行处置。开发了一个最小的基于生理的药代动力学（PBPK）模型来描述单克隆抗体在人体内的药代动力学。在该模型中，身体被分为三个生理隔室：血浆、单个组织隔室和淋巴。组织隔室进一步细分为血管、内皮和间质空间。该模型同时描述了每个隔室和子隔室内内源性IgG和外源性单克隆抗体的水平，特别是考虑了这两种物质在内皮空间中对FcRn结合的竞争。采用蒙特卡罗抽样方法模拟人群中内源性IgG和单克隆抗体的浓度。现有的靶点介导的药物处置（TMDD）模型与最小PBPK模型相结合，以提供一个通用平台，主要使用临床前数据输入来模拟治疗性抗体的药代动力学。研究了利用临床前数据对模型进行参数化并模拟阿达木单抗和一种抗ALK1抗体（PF-03446962）在个体人群中药代动力学的可行性，并将结果与已发表的临床数据进行比较。
