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人群药代动力学/药效动力学模型,用于 ESA 初治和 ESA 治疗的慢性肾脏病伴肾性贫血患者的 C.E.R.A.。

Population pharmacokinetic/pharmacodynamic model for C.E.R.A. in both ESA-naive and ESA-treated chronic kidney disease patients with renal anemia.

机构信息

PharmD, Pharsight - A Certara Company, Lyon, France.

出版信息

J Clin Pharmacol. 2010 May;50(5):507-20. doi: 10.1177/0091270009343931. Epub 2010 Feb 23.

Abstract

This study aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model for C.E.R.A., a continuous erythropoietin receptor activator. C.E.R.A. is administered via intravenous (IV) and subcutaneous (SC) routes once every 2 weeks (Q2W) or once every 4 weeks (Q4W), respectively, to correct or maintain hemoglobin levels in chronic kidney disease (CKD) patients. Population models were specified to describe C.E.R.A. (PK) and hemoglobin (PD) concentrations over time, using data from 3 phase III, open-label, randomized, parallel-group, multicenter studies that examined IV or SC C.E.R.A. administration Q2W and Q4W in erythropoiesis-stimulating agent (ESA)-naive and ESA-treated patients. C.E.R.A. PK was described by a 1-compartment model: drug clearance = 0.75 L/d, volume of distribution = 4.72 L, and half-life = 105 hours in accordance with previous reported values. The PD model, a life span sequential PK/PD model, adequately described hemoglobin data. Dosing schedule, administration route, and study type did not affect drug-related PD parameters or system-specific parameters (eg, red blood cell life span). This model adequately described C.E.R.A.'s PK and PD properties according to C.E.R.A. posology, thus permitting simulations exploring alternative drug administration scenarios. It supports use of C.E.R.A. IV and SC; Q2W for anemia correction in ESA-Naïve CKD patients and monthly administration in the hemoglobin maintenance phase.

摘要

本研究旨在开发一种人群药代动力学/药效学(PK/PD)模型,用于 C.E.R.A.,一种持续的促红细胞生成素受体激活剂。C.E.R.A. 通过静脉(IV)和皮下(SC)途径给药,分别每 2 周(Q2W)或每 4 周(Q4W)一次,以纠正或维持慢性肾脏病(CKD)患者的血红蛋白水平。使用来自 3 项 III 期、开放标签、随机、平行组、多中心研究的数据,指定人群模型来描述 C.E.R.A.(PK)和血红蛋白(PD)随时间的浓度,这些研究检查了 IV 或 SC C.E.R.A.在 ESA-初治和 ESA 治疗患者中的 Q2W 和 Q4W 给药。C.E.R.A. PK 由一个 1 室模型描述:药物清除率 = 0.75 L/d,分布容积 = 4.72 L,半衰期 = 105 小时,符合先前报道的值。PD 模型,即寿命顺序 PK/PD 模型,适当地描述了血红蛋白数据。给药方案、给药途径和研究类型均不影响与药物相关的 PD 参数或系统特异性参数(例如,红细胞寿命)。该模型根据 C.E.R.A. 给药方案充分描述了 C.E.R.A.的 PK 和 PD 特性,从而支持探索替代药物给药方案的模拟。它支持使用 C.E.R.A.IV 和 SC;ESA-初治 CKD 患者用于贫血纠正的 Q2W 和血红蛋白维持阶段的每月给药。

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