Krzyzanski Wojciech, Wyska Elzbieta
Department of Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14260, USA.
Naunyn Schmiedebergs Arch Pharmacol. 2008 Jun;377(4-6):637-45. doi: 10.1007/s00210-007-0225-z. Epub 2007 Dec 11.
The purpose of this study was to apply the target-mediated drug disposition (TMDD) pharmacokinetic (PK) model to describe binding, internalization, and turnover of erythropoietin receptor (EPOR). This model allows one to determine from free drug (C) PK data not only parameters describing linear disposition of EPO such as the elimination rate constant (kel) and volume of distribution (Vc), but also the total receptor concentration (Rtot0), drug-receptor complex (RC) internalization rate constant (kint), as well as synthesis and degradation rate constants (ksyn and kdeg) for the receptor turnover. The previously published data on PK of recombinant EPO (rHuEPO) in humans and the results of EPOR binding studies were used for analysis. The estimated PK parameters were used to simulate time courses of free and bound EPOR after IV administration of clinically relevant rHuEPO doses. The estimates of kel=0.106 h(-1) and Vc=0.032 l/kg are consistent with reported in the literature values of rHuEPO linear disposition parameters. The determined value of Rtot0 was 66.35 pM and the half-life for EPOR degradation was 8.8 h. Computer simulations showed a very rapid binding phase in the EPOR time profile followed by a decline to a nadir, and a subsequent return to the baseline. The nadir values decreased with increasing doses and resulted in the maximum values of the bound fractions of the total EPOR in the ranges 33-99%. At the baseline conditions, only 3.1% of EPOR were occupied. The saturation of EPOR was correlated with the time C remained above the KD level. In conclusion, the time courses of serum rHuEPO concentrations contain information about internalization and turnover of EPOR. Kinetics of EPOR can be utilized to determine the relationship between the pharmacologic effect and exposure to rHuEPO.
本研究的目的是应用靶点介导的药物处置（TMDD）药代动力学（PK）模型来描述促红细胞生成素受体（EPOR）的结合、内化和周转。该模型不仅能根据游离药物（C）的PK数据确定描述促红细胞生成素线性处置的参数，如消除速率常数（kel）和分布容积（Vc），还能确定总受体浓度（Rtot0）、药物 - 受体复合物（RC）内化速率常数（kint），以及受体周转的合成和降解速率常数（ksyn和kdeg）。分析使用了先前发表的重组促红细胞生成素（rHuEPO）在人体中的PK数据以及EPOR结合研究的结果。估计的PK参数用于模拟静脉注射临床相关rHuEPO剂量后游离和结合的EPOR的时间进程。kel = 0.106 h(-1)和Vc = 0.032 l/kg的估计值与文献报道的rHuEPO线性处置参数值一致。确定的Rtot0值为66.35 pM，EPOR降解的半衰期为8.8小时。计算机模拟显示，EPOR时间曲线中有一个非常快速的结合阶段，随后下降至最低点，然后再回到基线。最低点值随剂量增加而降低，导致总EPOR结合分数的最大值在33 - 99%范围内。在基线条件下，只有3.1%的EPOR被占据。EPOR的饱和度与C保持高于KD水平的时间相关。总之，血清rHuEPO浓度的时间进程包含有关EPOR内化和周转的信息。EPOR的动力学可用于确定药理效应与rHuEPO暴露之间的关系。
