Division of Pharmaceutics, College of Pharmacy, University of Iowa, 115 S. Grand Ave., Iowa City, IA 52242, USA.
Drug Metab Dispos. 2011 Apr;39(4):603-9. doi: 10.1124/dmd.110.036236. Epub 2011 Jan 5.
The pharmacokinetics (PK) of continuous erythropoietin receptor activator (CERA), a PEGylated erythropoietin (EPO) derivative, was studied in sheep after bone marrow (BM) busulfan ablation by using a receptor-based recirculation model and tracer interaction method (TIM) experiments. The nontracer CERA component of the TIM was analyzed using a noncompartmental approach. In contrast to EPO elimination that is linear after the BM ablation, CERA elimination remains nonlinear. After busulfan treatment, initial EPO receptors (EPOR) normalized production rate constant, EPOR degradation rate constant, and CERA-EPOR complex internalization rate constant decreased (p < 0.01), whereas no change in CERA/EPOR equilibrium dissociation constant was detected (p > 0.05). After BM ablation, noncompartmental analysis showed that CERA-PK parameters underwent 1) a decrease in plasma clearance (p < 0.01); 2) a concomitant increase in elimination half-life and mean residence time; and 3) no significant change in volume of distribution, distribution half-life, or distributional clearance (p > 0.05). These results suggest that CERA elimination is mediated through saturable hematopoietic and nonhematopoietic EPOR pathways, with possible contribution of another EPOR-independent pathway(s). Compared with the nonhematopoietic EPOR population, the hematopoietic receptors have similar affinity to CERA but are significantly more involved in CERA's in vivo elimination. The saturable nature of the nonerythropoietic, non-BM pathway(s) for CERA in contrast to EPO predicts two fundamental differences: 1) an increasing fraction of CERA is used for erythropoiesis for increasing concentrations; and 2) the clearance of CERA becomes more limited for increasing concentrations. Taken together, these differences favor a more efficacious and prolonged action for CERA.
连续促红细胞生成素受体激活剂（CERA）是一种聚乙二醇化的促红细胞生成素（EPO）衍生物，其药代动力学（PK）在羊骨髓（BM）白消安消融后通过基于受体的再循环模型和示踪剂相互作用方法（TIM）实验进行了研究。TIM 中的非示踪剂 CERA 成分使用非房室方法进行分析。与 BM 消融后 EPO 消除呈线性不同，CERA 消除仍呈非线性。在白消安处理后，初始 EPO 受体（EPOR）正常化产生率常数、EPOR 降解率常数和 CERA-EPOR 复合物内化率常数降低（p<0.01），而 CERA/EPOR 平衡解离常数没有变化（p>0.05）。BM 消融后，非房室分析显示 CERA-PK 参数发生了 1）血浆清除率降低（p<0.01）；2）消除半衰期和平均停留时间增加；3）分布容积、分布半衰期或分布清除率无显著变化（p>0.05）。这些结果表明，CERA 消除是通过饱和的造血和非造血 EPOR 途径介导的，可能还有其他 EPOR 独立途径的贡献。与非造血 EPOR 群体相比，造血受体对 CERA 具有相似的亲和力，但在 CERA 的体内消除中参与程度更高。与 EPO 相比，CERA 的非红细胞生成、非 BM 途径的饱和性质预测了两个基本区别：1）随着浓度的增加，CERA 用于红细胞生成的比例增加；2）随着浓度的增加，CERA 的清除变得更加有限。综上所述，这些差异有利于 CERA 更有效和更持久的作用。
