Faculté de Pharmacie, Neuropsychopharmacologie des Addictions, Université Paris Descartes, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Paris, France.
J Pharmacol Exp Ther. 2010 Sep 1;334(3):897-910. doi: 10.1124/jpet.110.167304. Epub 2010 May 25.
A pharmacokinetics (PK)/pharmacodynamics (PD) model was developed to describe the tolerance and rebound for reticulocyte (RET) and red blood cell (RBC) counts and the hemoglobin (Hb) concentrations in blood after repeated intravenous administrations of 1350 IU/kg of recombinant human erythropoietin (rHuEPO) in rats thrice weekly for 6 weeks. Drug concentrations were described by using a quasi-equilibrium model. The PD model consisted of a lifespan-based indirect response model (LIDR) with progenitor cells [burst colony-forming unit erythroblasts and colony-forming unit erythroblasts (CFUs)], normoblasts (NOR), RETs, and RBCs. Drug-receptor complex stimulatory effects on progenitor cells differentiation and RBC lifespan were expressed by using the E(max) model (S(max-epo) and SC(50-epo), E(max) and EC(50)). The Hb profile was indirectly modeled through a LIDR model for mean corpuscular hemoglobin (with a lifespan T(mch)) including a linear (S(max-mch)) drug stimulatory effect. The negative feedback from RBCs accounted for the time-dependent rHuEPO clearance decline. A simultaneous PK/PD fitting was performed by using MATLAB-based software. PK parameters such as equilibrium dissociation, erythropoietin receptor degradation, production, and internalization rate constants were 0.18 nM (fixed), 0.08 h(-1), 0.03 nM/h, and 2.51 h(-1), respectively. The elimination rate constant and central volume of distribution were 0.57 h(-1) and 40.63 ml/kg, respectively. CFU and NOR, RET, and RBC lifespans were 37.26 h, 17.25 h, and 30.15 days, respectively. S(max-epo) and SC(50-epo) were 7.3 and 0.47 10(-2) nM, respectively. E(max) was fixed to 1. EC(50) and SC(50-epo) were equal. S(max-mch) and T(mch) were 168.1 nM(-1) and 35.15 days, respectively. The proposed PK/PD model effectively described rHuEPO nonstationary PK and allowed physiological estimates of cell lifespans.
建立了药代动力学（PK）/药效动力学（PD）模型，以描述大鼠每周 3 次静脉内给予 1350IU/kg 重组人促红细胞生成素（rHuEPO）6 周后，网织红细胞（RET）和红细胞（RBC）计数以及血液中血红蛋白（Hb）浓度的耐受性和反弹。使用准平衡模型描述药物浓度。PD 模型由基于寿命的间接反应模型（LIDR）组成，其中包括祖细胞[集落形成单位红细胞母细胞和集落形成单位红细胞（CFUs）]、成核细胞（NOR）、RET 和 RBC。通过 E（max）模型（S（max-epo）和 SC（50-epo）、E（max）和 EC（50））表示药物-受体复合物对祖细胞分化和 RBC 寿命的刺激作用。通过 LIDR 模型间接模拟 Hb 谱，用于平均红细胞血红蛋白（具有寿命 T（mch）），包括线性（S（max-mch））药物刺激作用。RBC 的负反馈解释了 rHuEPO 清除率随时间下降的原因。通过使用基于 MATLAB 的软件进行同时 PK/PD 拟合。PK 参数，如平衡解离、促红细胞生成素受体降解、产生和内化速率常数分别为 0.18nM（固定）、0.08h（-1）、0.03nM/h 和 2.51h（-1）。消除速率常数和中心分布体积分别为 0.57h（-1）和 40.63ml/kg。CFU 和 NOR、RET 和 RBC 寿命分别为 37.26h、17.25h 和 30.15 天。S（max-epo）和 SC（50-epo）分别为 7.3 和 0.47×10（-2）nM。E（max）固定为 1。EC（50）和 SC（50-epo）相等。S（max-mch）和 T（mch）分别为 168.1nM（-1）和 35.15 天。所提出的 PK/PD 模型有效地描述了 rHuEPO 非稳态 PK，并允许对细胞寿命进行生理估计。
