Population pharmacokinetics and pharmacodynamics of inhaled ciclesonide and fluticasone propionate in patients with persistent asthma.

Abstract

Inhaled corticosteroids, such as fluticasone propionate (FP) and ciclesonide (CIC), are commonly used for the treatment of asthma. The objectives of this study were to characterize pharmacokinetics (PK) and pharmacodynamics (PD) of FP and a pharmacologically active metabolite of CIC (desisobutyryl-ciclesonide [Des-CIC]) using a nonlinear mixed-effects modeling approach, to investigate selected covariate effects on PK and PD parameters of FP and Des-CIC, and to assess the systemic effects of FP and CIC on serum cortisol suppression in patients with persistent asthma. This was a randomized, double-blind, placebo-controlled, double-dummy, 5-period, crossover, multicenter clinical study. A total of 32 patients were enrolled and given basic asthma medication (salmeterol 50 µg twice per day [BID] and CIC 160 µg daily in the evening) through the entire study. During crossover periods, patients were given placebo or CIC 160 µg BID (ex actuator), CIC 320 µg BID (ex actuator), FP 220 µg BID (ex actuator), or FP 440 µg BID (ex actuator). The FP and Des-CIC PK were described using a 1-compartment and a 2-compartment linear model with first-order absorption process. The FP population PK parameter estimates of the first-order rate constant, relative clearance, and volume of distribution were 4.07 1/h, 890 L/h, and 9800 L, respectively. The Des-CIC PK parameter estimates of the first-order absorption rate constant were 2.63 1/h, clearance 202 L/h (non-CIC treatment) or 271 L/h (CIC treatment), and volume of distribution 947 L. Gender was a significant covariate on the maximum cortisol release rate (male, 3440 µg/h; female, 4310 µg/h). The CIC showed the least serum cortisol suppression of the tested dosing regimens.

• Authors: Jian Xu, Rüdiger Nave, Gezim Lahu, Eric Derom, Hartmut Derendorf
• Journal: Journal of clinical pharmacology (J Clin Pharmacol) Vol. 50 Issue 10 Pg. 1118-27 (Oct 2010) ISSN: 1552-4604 [Electronic] England
• PMID: 20150524 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Androstadienes
• Anti-Allergic Agents
• Bronchodilator Agents
• Pregnenediones
• Salmeterol Xinafoate
• desisobutyrylciclesonide
• Fluticasone
• Albuterol
• ciclesonide
• Hydrocortisone

Topics

• Administration, Inhalation
• Adult
• Albuterol (administration & dosage, analogs & derivatives, therapeutic use)
• Androstadienes (administration & dosage, pharmacokinetics, therapeutic use)
• Anti-Allergic Agents (administration & dosage, pharmacokinetics, therapeutic use)
• Area Under Curve
• Asthma (drug therapy)
• Bronchodilator Agents (administration & dosage, therapeutic use)
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Double-Blind Method
• Female
• Fluticasone
• Half-Life
• Humans
• Hydrocortisone (blood)
• Male
• Middle Aged
• Pregnenediones (administration & dosage, pharmacokinetics, therapeutic use)
• Salmeterol Xinafoate
• Sex Factors