Laboratoire de Pharmacocinétique Clinique, Faculté de Pharmacie, Université Montpellier I, BP 14491, 34093, Montpellier, Cedex 5, France.
Clin Drug Investig. 2003;23(3):167-79. doi: 10.2165/00044011-200323030-00003.
To develop a pharmacokinetic model able to take into account the negative feedback loop of endogenous erythropoietin production observed after repeated administration of recombinant human erythropoietin (rHuEPO), and to propose a pharmacokinetic-pharmacodynamic model capable of assessing and quantifying the relationship between changes in: (i) serum soluble transferrin receptor (sTfR) levels, (ii) reticulocyte haematocrit (RetHct), and (iii) percentage macrocytes (%Macro) secondary to repeated administration of rHuEPO.
Eighteen trained athletes (three females and 15 males) participated in this study. They received subcutaneous injections of rHuEPO-α 50 U/kg bodyweight for 26 days (days 1, 3, 5, 9, 10, 12, 15, 17, 19, 22, 24 and 26) with iron supplementation. Venous blood samples were collected before, during and after rHuEPO treatment for determination of serum erythropoietin concentrations, haematological parameters (RetHct, %Macro) and sTfR levels. Population pharmacokinetic-pharmacodynamic calculations were performed using NONMEM® software.
The serum erythropoietin concentration-time profile was compatible with a one-compartment open model and first-order input rate. The mean half-lives calculated from the first and the terminal log-linear parts of the curves were 5.2 and 35.8 hours, respectively. After subcutaneous administration of rHuEPO, the terminal part of the curve should correspond to the absorption rather than the elimination phase ('flip-flop' phenomenon). The total clearance divided by bio-availability was 4.33 L/h. The pharmacodynamic relationship based on a sigmoid E(max) model can be reasonably used to relate changes observed in haematological and biochemical markers after rHuEPO administration to changes in serum erythropoietin concentrations. rHuEPO induces a delayed increase in sTfR levels, RetHct and %Macro. The half-life (t1/2) k(0) (equilibration delay) values were 10.2 days for sTfR, 2 days for RetHct and 10.2 days for %Macro. The pharmaco-kinetic-pharmacodynamic approach developed in this study allowed below-base-line decreases in RetHct levels (i.e. from days 10-26 after the end of rHuEPO treatment) to be taken into account. A negative-feedback loop of red blood cell production further to high haemoglobin and haematocrit values could explain this decrease.
The approach described here may provide an additional tool in the war against drug abuse by athletes; indeed, the model could be useful for simulating pharmacokinetic-pharmacodynamic relationships according to different rHuEPO dosage schedules.
开发一种药代动力学模型，能够考虑到重组人促红细胞生成素（rHuEPO）重复给药后内源性促红细胞生成素产生的负反馈环，并提出一种药代动力学-药效学模型，能够评估和量化以下变化之间的关系：（i）血清可溶性转铁蛋白受体（sTfR）水平，（ii）网织红细胞血细胞比容（RetHct），和（iii）重复给予 rHuEPO 后 %Macro 的变化。
18 名训练有素的运动员（3 名女性和 15 名男性）参加了这项研究。他们接受了 rHuEPO-α 50 U/kg 体重的皮下注射，共 26 天（第 1、3、5、9、10、12、15、17、19、22、24 和 26 天），同时进行铁补充。在 rHuEPO 治疗前后采集静脉血样，用于测定血清促红细胞生成素浓度、血液学参数（RetHct、%Macro）和 sTfR 水平。使用 NONMEM®软件进行群体药代动力学-药效学计算。
血清促红细胞生成素浓度-时间曲线与单室开放模型和一级输入速率相匹配。从曲线的第一和末端对数线性部分计算的平均半衰期分别为 5.2 和 35.8 小时。皮下给予 rHuEPO 后，曲线的末端部分应对应于吸收而不是消除相（“翻转”现象）。总清除率除以生物利用度为 4.33 L/h。基于 sigmoid E(max)模型的药效关系可以合理地用于将 rHuEPO 给药后观察到的血液学和生化标志物的变化与血清促红细胞生成素浓度的变化联系起来。rHuEPO 诱导 sTfR 水平、RetHct 和 %Macro 的延迟增加。sTfR 的半衰期（t1/2）k(0)（平衡延迟）值为 10.2 天，RetHct 为 2 天，%Macro 为 10.2 天。本研究中开发的药代动力学-药效学方法允许考虑 rHuEPO 治疗结束后 10-26 天 RetHct 水平低于基线的下降。对高血红蛋白和血细胞比容值的红细胞生成的负反馈环可以解释这种下降。
这里描述的方法可能为打击运动员药物滥用提供另一种工具；事实上，该模型可用于根据不同的 rHuEPO 剂量方案模拟药代动力学-药效学关系。
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