Population pharmacokinetics and pharmacodynamics of ciclesonide
Population pharmacokinetics and pharmacodynamics of ciclesonide
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DOI：
10.1177/0091270002250998
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发表时间：
2003-04-01
影响因子：
2.9
通讯作者：
Barrett, JS
中科院分区：
文献类型：
--
作者：
Rohatagi, S;Arya, V;Barrett, JS
环索奈德是一种新型糖皮质激素，在肺中转化为环索奈德活性成分（CIC-AP）。研究目的是使用非线性混合效应建模确定CIC-AP群体药代动力学（PK）分析的结构模型，评估选定协变量对PK和/或药效学（PD）参数的影响，并研究CIC-AP对内源性皮质醇的影响。PK分析中纳入了9项涉及健康和哮喘患者的I期研究（剂量：400-3600 μ g）的汇总浓度数据。CIC-AP群体PK分析有151例受试者（3300个观察结果）。各种模型检查了PK参数的受试者间和受试者内变异性。清除率和分布容积PK参数的群体估计值分别为396 L/h（64.8%变异系数[CV]）和1190 L（41.2% CV）。药效学群体估计值包括最大皮质醇释放速率，3140 ng/h（5.4% CV）。CIC-AP的EC_（50）为0.88 ng/mL。环索奈德是一种安全的皮质类固醇，对皮质醇的抑制作用可以忽略不计。CIC-AP的配置和效果可以使用混合效应模型来描述。估计的EC 50与800 μ g剂量的平均C-max相似，进一步表明CIC-AP对皮质醇抑制作用很小。
Ciclesonide is a novel glucocorticoid that is converted into ciclesonide-active principle (CIC-AP) in the lung. The study objectives were to identify a structural model for population pharmacokinetic (PK) analysis of CIC-AP using nonlinear mixed-effects modeling, assess the influence of select covariates on PK and/or pharmacodynamic (PD)parameters, and investigate the effects of CIC-AP on endogenous cortisol. Pooled concentration data from nine phase I studies (dose: 400-3600 mug) involving healthy and asthmatic patients were included in the PK analysis. There were 151 subjects (3300 observations) for the CIC-AP population PK analysis. Various models examined inter- and intrasubject variability for the PK parameters. Population estimates of the PK parameters of clearance and volume of distribution were 396 L/h (64.8% co-efficient of variation [CV]) and 1190 L (41.2% CV), respectively. Pharmacodynamic population estimates included maximum cortisol release rate, 3140 ng/h (5.4% CV). The EC50 of CIC-AP was 0.88 ng/mL. Ciclesonide is a safe corticosteroid that causes negligible cortisol suppression. The disposition and effect of CIC-AP can be described using mixed-effect modeling. The estimated EC50 is similar to mean C-max from an 800-mug dose, further suggesting CIC-AP has little effect on cortisol suppression.