Population pharmacokinetics and pharmacodynamics of ciclesonide.
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 micrograms) 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 Cmax from an 800-micrograms dose, further suggesting CIC-AP has little effect on cortisol suppression.
Rohatagi
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Aventis Pharmaceuticals Mail Stop: BWM-203F, Route 202-206, P.O. Box 6800, Bridgewater, NJ 08807-0800, USA.
Arya
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Zech
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Nave
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Hochhaus
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Jensen
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Barrett
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D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D003627:Data Interpretation, Statistical; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011282:Pregnenediones / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*
D018927:Anti-Asthmatic Agents; D011282:Pregnenediones; C120481:ciclesonide; D006854:Hydrocortisone