Population Pharmacokinetics and Pharmacodynamics of Ciclesonide

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Abstract
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 μg) 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% coefficient 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 Cmax from an 800–μg dose, further suggesting CIC‐AP has little effect on cortisol suppression.