Naik Himanshu, Tsai Max C, Fiedler-Kelly Jill, Qiu Ping, Vakilynejad Majid
Pharmacometrics, Takeda Global Research and Development, Inc., Deerfield, Illinois, United States of America.
PLoS One. 2013 Jun 19;8(6):e66422. doi: 10.1371/journal.pone.0066422. Print 2013.
Peginesatide (OMONTYS®) is an erythropoiesis-stimulating agent that was indicated in the United States for the treatment of anemia due to chronic kidney disease in adult patients on dialysis prior to its recent marketing withdrawal by the manufacturer. The objective of this analysis was to develop a population pharmacokinetic and pharmacodynamic model to characterize the time-course of peginesatide plasma and hemoglobin concentrations following intravenous and subcutaneous administration. Plasma samples (n = 2,665) from 672 patients with chronic kidney disease (on or not on dialysis) and hemoglobin samples (n = 18,857) from 517 hemodialysis patients (subset of the 672 patients), were used for pharmacokinetic-pharmacodynamic model development in NONMEM VI. The pharmacokinetic profile of peginesatide was best described by a two-compartment model with first-order absorption and saturable elimination. The relationship between peginesatide and hemoglobin plasma concentrations was best characterized by a modified precursor-dependent lifespan indirect response model. The estimate of maximal stimulatory effect of peginesatide on the endogenous production rate of progenitor cells (Emax) was 0.54. The estimate of peginesatide drug concentration required for 50% of maximal response (EC50) estimates was 0.4 µg/mL. Several significant (P<0.005) covariates affected simulated peginesatide exposure by ≤36%. Based upon ≤0.2 g/dL effects on simulated hemoglobin levels, none were considered clinically relevant.
聚乙二醇化促红细胞生成素（OMONTYS®）是一种促红细胞生成剂，在其制造商最近撤市之前，在美国被用于治疗接受透析的成年慢性肾病患者的贫血。本分析的目的是建立一个群体药代动力学和药效学模型，以描述静脉注射和皮下注射后聚乙二醇化促红细胞生成素血浆浓度和血红蛋白浓度随时间的变化过程。来自672例慢性肾病患者（透析或未透析）的血浆样本（n = 2665）和来自517例血液透析患者（672例患者的子集）的血红蛋白样本（n = 18857）用于NONMEM VI中的药代动力学-药效学模型开发。聚乙二醇化促红细胞生成素的药代动力学特征最好用具有一级吸收和饱和消除的二室模型来描述。聚乙二醇化促红细胞生成素与血红蛋白血浆浓度之间的关系最好用改良的前体依赖性寿命间接反应模型来表征。聚乙二醇化促红细胞生成素对祖细胞内源性产生率的最大刺激作用（Emax）估计值为0.54。达到最大反应50%所需的聚乙二醇化促红细胞生成素药物浓度（EC50）估计值为0.4μg/mL。几个显著（P<0.005）的协变量对模拟的聚乙二醇化促红细胞生成素暴露的影响≤36%。基于对模拟血红蛋白水平≤0.2 g/dL的影响，没有一个被认为具有临床相关性。
