Varlet-Marie E, Gaudard A, Audran M, Gomeni R, Bressolle F
Laboratoire de Pharmacocinétique Clinique, Faculté de Pharmacie, Université Montpellier I, France.
Int J Sports Med. 2003 May;24(4):252-7. doi: 10.1055/s-2003-39506.
The aim of this study was to develop a pharmacokinetic model that takes into account the negative feedback loop of endogenous erythropoietin production observed after repeated recombinant human erythropoietin administration. A pharmacodynamic data analysis was performed using the changes in i) reticulocyte count, ii) serum levels of soluble transferrin receptors, and iii) soluble transferrin receptors/serum proteins ratio as an index of the therapeutic effect of the hormone. Nine athletes were included in the study; they received repeated subcutaneous administrations (50 IU x kg(-1) per day) of recombinant human erythropoietin. The mean half-life of the terminal part of the curve was 35.5 h, and the total clearance was 17 ml x h(-1) x kg(-1). The total clearance was about two times higher in athletes than in untrained subjects (5.5 - 7.5 ml x h(-1) x kg(-1)) and the half-life period of plasma erythropoietin after subcutaneous administration was five times longer compared to intravenous administration (4 to 7 h). Thus, after subcutaneous administration, the terminal part of the curve should correspond to the absorption phase, instead of to the elimination phase (flip-flop phenomenon). The pharmacodynamic relationship based on a sigmoid Emax model can be reasonably used to relate the changes observed in the markers to recombinant human erythropoietin administration. Recombinant human erythropoietin induces a delayed increase in reticulocytosis and in soluble transferrin receptor levels. In comparison with baseline, the increase of these markers became significant from the third and the tenth day after the initial administration of the hormone, respectively. These results were in accordance with the equilibration delay computed from the pharmacokinetic-pharmacodynamic data modelling (half-life of 25.7 h and 10 days, respectively). The recombinant hormone was well tolerated during this study.
本研究的目的是建立一个药代动力学模型，该模型要考虑到重复给予重组人促红细胞生成素后所观察到的内源性促红细胞生成素产生的负反馈回路。使用以下指标进行药效学数据分析：i）网织红细胞计数的变化、ii）可溶性转铁蛋白受体的血清水平，以及iii）可溶性转铁蛋白受体/血清蛋白比值作为该激素治疗效果的指标。九名运动员被纳入该研究；他们接受了重组人促红细胞生成素的重复皮下给药（每天50 IU×kg⁻¹）。曲线终末部分的平均半衰期为35.5小时，总清除率为17 ml×h⁻¹×kg⁻¹。运动员的总清除率比未受过训练的受试者（5.5 - 7.5 ml×h⁻¹×kg⁻¹）高约两倍，皮下给药后血浆促红细胞生成素的半衰期比静脉给药时长五倍（4至7小时）。因此，皮下给药后，曲线的终末部分应对应于吸收相，而非消除相（翻转现象）。基于S型Emax模型的药效学关系可合理地用于将标志物中观察到的变化与重组人促红细胞生成素的给药联系起来。重组人促红细胞生成素诱导网织红细胞增多症和可溶性转铁蛋白受体水平的延迟升高。与基线相比，这些标志物的升高分别在首次给予该激素后的第三天和第十天变得显著。这些结果与从药代动力学 - 药效学数据建模计算出的平衡延迟一致（半衰期分别为25.7小时和10天）。在本研究期间，重组激素耐受性良好。
