Zhao Jie, Cao Yanguang, Jusko William J
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, New York, 14214, USA.
Pharm Res. 2015 Oct;32(10):3269-81. doi: 10.1007/s11095-015-1703-5. Epub 2015 May 5.
To examine the across-species scalability of monoclonal antibody (mAb) pharmacokinetics (PK) and assess similarities in tissue distribution across species using a recently developed minimal PBPK (mPBPK) model.
Twelve sets of antibody PK data from various species were obtained from the literature, which were jointly and individually analyzed. In joint analysis, vascular reflection coefficients for tissues with either tight (σ 1 ) or leaky endothelium (σ 2 ) were assumed consistent across species with systemic clearance allometrically scaled (CL = a∙BW (b) ). Four parameters (σ 1 , σ 2 , a, and b) were estimated in the joint analysis. In addition, the PK from each species was individually analyzed to assess species similarities in tissue distribution.
Twelve mAb PK profiles were well-captured by the mPBPK model in the joint analysis. The estimated σ 1 ranged 0.690 to 0.999 with an average of 0.908; and σ 2 ranged 0.258 to 0.841 with an average of 0.579. Clearance was reasonably scaled and b ranged 0.695 to 1.27 averaging 0.91. Predictions of plasma concentrations for erlizumab and canakinumab in humans using parameters obtained from fitting animal data were consistent with actual measurements.
Therapeutic mAbs given IV usually exhibit biexponential kinetics with their distribution properties best captured using physiological concepts. The mPBPK modeling approach may facilitate efforts in translating antibody distribution and overall PK across species.
使用最近开发的最小生理药代动力学（mPBPK）模型，研究单克隆抗体（mAb）药代动力学（PK）的跨物种可扩展性，并评估不同物种间组织分布的相似性。
从文献中获取了来自不同物种的12组抗体PK数据，对其进行联合分析和单独分析。在联合分析中，假设紧密内皮（σ1）或渗漏内皮（σ2）组织的血管反射系数在不同物种间是一致的，全身清除率按异速生长比例缩放（CL = a∙BW(b)）。在联合分析中估计了四个参数（σ1、σ2、a和b）。此外，对每个物种的PK进行单独分析，以评估组织分布中的物种相似性。
在联合分析中，mPBPK模型很好地捕捉了12个mAb的PK曲线。估计的σ1范围为0.690至0.999，平均为0.908；σ2范围为0.258至0.841，平均为0.579。清除率得到合理缩放，b范围为0.695至1.27，平均为0.91。使用从拟合动物数据获得的参数对人源埃利珠单抗和卡那单抗血浆浓度的预测与实际测量结果一致。
静脉注射治疗性单克隆抗体通常表现出双指数动力学，其分布特性最好用生理学概念来描述。mPBPK建模方法可能有助于跨物种转化抗体分布和整体药代动力学。
