Translational Research Group, Department of Pharmacokinetics Dynamics and Metabolism, Pfizer Global Research and Development Groton Labs, MS 8220-4573, Eastern Point Road, Groton, CT 06340, USA.
J Pharmacokinet Pharmacodyn. 2012 Feb;39(1):67-86. doi: 10.1007/s10928-011-9232-2. Epub 2011 Dec 6.
The objectives of the following investigation were (1) development of a physiologically based pharmacokinetic (PBPK) model capable of characterizing the plasma and tissue pharmacokinetics (PK) of nonspecific or antigen specific monoclonal antibodies (mAbs) in wild type, FcRn knockout, tumor bearing and non tumor bearing mice and (2) evaluation of the scale up potential of the model by characterizing the mouse, rat, monkey and human plasma PK of mAbs, simultaneously. A PBPK model containing 15 tissues, a carcass and a tumor compartment was developed by modifying/augmenting previously published PBPK models. Each tissue compartment was subdivided into plasma, blood cell, endothelial, interstitial and cellular sub-compartments. Each tissue was connected through blood and lymph flow to the systemic circulation. Lymph flow was set to a value 500 times lower than plasma flow and vascular reflection coefficients for each tissue were adjusted according to their vascular pore size. In each tissue endothelial space, mAb entered via pinocytosis and the interaction of FcRn with mAb was described by on and off rates. FcRn bound mAb was recycled and unbound mAb was eliminated by a first order process (K(deg)). The PBPK model was simultaneously fit to the following datasets to estimate four system parameters: (1) plasma and tissue PK of nonspecific mAb in wild type mouse with or without simultaneous intravenous immunoglobulin (IVIG) administration, (2) plasma and tissue PK of nonspecific mAb in FcRn knockout mouse, (3) plasma and tissue PK of nonspecific mAb in tumor bearing mouse, (4) plasma and tissue PK of tumor antigen specific mAb in tumor bearing mouse, and (5) plasma PK of mAb in rat, monkey and human. The model was able to characterize all the datasets reasonably well with a common set of parameters. The estimated value of the four system parameters i.e. FcRn concentration (FcRn), rate of pinocytosis per unit endosomal space (CL(up)), K(deg) and the proportionality constant (C_LNLF) between the rate at which antibody transfers from the lymph node compartment to the blood compartment and the plasma flow of the given species, were found to be 4.98E-05 M (CV% = 11.1), 3.66E-02 l/h/l (%CV = 3.48), 42.9 1/h (%CV = 15.7) and 9.1 (CV% > 50). Thus, a platform PBPK model has been developed that can not only simultaneously characterize mAb disposition data obtained from various previously published mouse PBPK models but is also capable of characterizing mAb disposition in various preclinical species and human.
本研究的目的是（1）开发一种能够描述野生型、FcRn 敲除、荷瘤和非荷瘤小鼠中非特异性或抗原特异性单克隆抗体（mAb）的血浆和组织药代动力学（PK）的基于生理学的药代动力学（PBPK）模型；（2）通过同时描述 mAb 在小鼠、大鼠、猴子和人体内的 PK，评估模型的放大潜力。通过修改/扩充先前发表的 PBPK 模型，开发了一个包含 15 个组织、一个尸骸和一个肿瘤隔室的 PBPK 模型。每个组织隔室被细分为血浆、血细胞、内皮细胞、细胞间和细胞亚隔室。每个组织通过血流和淋巴流与全身循环相连。淋巴流量设定为血浆流量的 500 倍，并且根据其血管孔径调整每个组织的血管反射系数。在每个组织的内皮空间中，mAb 通过胞饮作用进入，并且 FcRn 与 mAb 的相互作用通过结合和解离速率来描述。FcRn 结合的 mAb 被回收，未结合的 mAb 通过一级过程（Kdeg）被消除。该 PBPK 模型同时拟合以下数据集以估计四个系统参数：（1）野生型小鼠中无特异性 mAb 或同时静脉注射免疫球蛋白（IVIG）给药时的血浆和组织 PK；（2）FcRn 敲除小鼠中无特异性 mAb 的血浆和组织 PK；（3）荷瘤小鼠中无特异性 mAb 的血浆和组织 PK；（4）荷瘤小鼠中肿瘤抗原特异性 mAb 的血浆和组织 PK；（5）大鼠、猴子和人体内 mAb 的血浆 PK。该模型能够用一组共同的参数很好地描述所有数据集。估计的四个系统参数的值，即 FcRn 浓度（FcRn）、每个内体空间的胞饮速率（CLup）、Kdeg 和抗体从淋巴结隔室转移到血流隔室的速率与特定物种的血浆流量之间的比例常数（C_LNLF），分别为 4.98E-05 M（CV% = 11.1）、3.66E-02 l/h/l（%CV = 3.48）、42.9 1/h（%CV = 15.7）和 9.1（CV%>50）。因此，开发了一种平台 PBPK 模型，不仅能够同时描述从各种先前发表的小鼠 PBPK 模型获得的 mAb 处置数据，而且能够描述各种临床前物种和人体内的 mAb 处置。
