Population Pharmacokinetics and Pharmacodynamics of Inhaled Ciclesonide and Fluticasone Propionate in Patients With Persistent Asthma

• Published in: Journal of clinical pharmacology 2010-10, Vol.50 (10), p.1118-1127
• Main Authors: Xu, Jian, Nave, Rüdiger, Lahu, Gezim, Derom, Eric, Derendorf, Hartmut
• Format: Article
• Language: English
• Subjects: Administration, Inhalation; Adult; Albuterol - administration & dosage; Albuterol - analogs & derivatives; Albuterol - therapeutic use; Androstadienes - administration & dosage; Androstadienes - pharmacokinetics; Androstadienes - therapeutic use; Anti-Allergic Agents - administration & dosage; Anti-Allergic Agents - pharmacokinetics; Anti-Allergic Agents - therapeutic use; Area Under Curve; asthma; Asthma - drug therapy; Bronchodilator Agents - administration & dosage; Bronchodilator Agents - therapeutic use; ciclesonide; cortisol suppression; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluticasone; fluticasone propionate; Half-Life; Humans; Hydrocortisone - blood; inhaled corticosteroids; Male; Middle Aged; Population pharmacokinetics and pharmacodynamics; Pregnenediones - administration & dosage; Pregnenediones - pharmacokinetics; Pregnenediones - therapeutic use; Salmeterol Xinafoate; Sex Factors
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1177/0091270009354994

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.