Woo Sukyung, Krzyzanski Wojciech, Jusko William J
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, 565 Hochstetter Hall, State University of New York at Buffalo, Buffalo, NY 14260, USA.
J Pharmacol Exp Ther. 2006 Dec;319(3):1297-306. doi: 10.1124/jpet.106.111377. Epub 2006 Sep 14.
The pharmacokinetics (PK) and pharmacodynamics (PD) of recombinant human erythropoietin (rHuEPO) were studied in rats after single i.v. and s.c. administration at three dose levels (450, 1350, and 4050 IU/kg). The plasma concentrations of rHuEPO and its erythropoietic effects including reticulocyte (RET), red blood cell (RBC), and hemoglobin (Hb) levels were determined. A two-compartment model with dual input rate and nonlinear disposition was used to characterize the PK of rHuEPO. The catenary indirect response model with several compartments reflecting the bone marrow and circulating erythropoietic cells was applied. The s.c. doses exhibited slow absorption (T(max) = 12 h) and incomplete bioavailability (F = 0.59). In placebo groups, RBC and Hb values gradually increased over time with growth of the rats, and the changes in the baselines monitored from 8 to 32 weeks of age were described by a nonlinear growth function. All doses resulted in dose-dependent increases in RET counts followed by an immediate decline below the baseline at around 6 days and returned to the predose level in 21-24 days after dosing. A subsequent steady increase of RBC and Hb levels followed and reached peaks at 6 days. A tolerance phenomenon observed at all dose levels was modeled by a negative feedback inhibition with the relative change in Hb level. The PK/PD model well described the erythropoietic effects of rHuEPO as well as tolerance, thereby yielding important PD parameters (S(max) = 1.87 and SC(50) = 65.37 mIU/ml) and mean lifespans of major erythropoietic cell populations in rats.
在大鼠中，以三种剂量水平（450、1350和4050 IU/kg）单次静脉注射和皮下注射重组人促红细胞生成素（rHuEPO）后，对其药代动力学（PK）和药效动力学（PD）进行了研究。测定了rHuEPO的血浆浓度及其促红细胞生成作用，包括网织红细胞（RET）、红细胞（RBC）和血红蛋白（Hb）水平。采用具有双输入速率和非线性处置的二室模型来表征rHuEPO的PK。应用具有反映骨髓和循环促红细胞生成细胞的多个隔室的链式间接反应模型。皮下注射剂量表现出吸收缓慢（T(max)=12小时）和生物利用度不完全（F = 0.59）。在安慰剂组中，随着大鼠生长，RBC和Hb值随时间逐渐增加，8至32周龄监测的基线变化用非线性生长函数描述。所有剂量均导致RET计数呈剂量依赖性增加，随后在约6天时立即降至基线以下，并在给药后21 - 24天恢复到给药前水平。随后RBC和Hb水平持续稳定升高，并在6天时达到峰值。在所有剂量水平观察到的耐受性现象通过Hb水平相对变化的负反馈抑制进行建模。PK/PD模型很好地描述了rHuEPO的促红细胞生成作用以及耐受性，从而得出重要的PD参数（S(max)=1.87和SC(50)=65.37 mIU/ml）以及大鼠主要促红细胞生成细胞群体的平均寿命。
