An investigation of the pharmacokinetics, pharmacodynamics, safety, and tolerability of ciclesonide hydrofluoroalkane nasal aerosol in healthy subjects and subjects with perennial allergic rhinitis.

摘要

Ciclesonide hydrofluoroalkane nasal aerosol (CIC-HFA) is currently in development for treatment of allergic rhinitis. This Phase I study evaluated the pharmacokinetics, pharmacodynamics, safety, and tolerability of CIC-HFA in healthy subjects (N = 18) and subjects with perennial allergic rhinitis (PAR, N = 18) in a double-blind, placebo-controlled, 3-period crossover design following treatment with 282 mug or 148 mug CIC-HFA or placebo once-daily for 14 days. The concentrations of desisobutyryl-ciclesonide (des-CIC), the pharmacologically active metabolite of CIC were measured by a validated high performance liquid chromatography with tandem mass spectrometry. Maximum serum concentration (C(max)), area under the serum concentration time curve (AUC), time to maximum serum concentration (t(max)) and elimination half life (t(1/2)) where feasible, were calculated. Serum cortisol (AUC(0-24h)) and adverse events (AE) were also evaluated. The overall systemic exposure of des-CIC was low. The mean C(max) for des-CIC on Day 14 was 35.84 ng/L and 25.98 ng/L for the CIC-HFA 282 mug and CIC-HFA 148 mug treatment groups respectively. Mean AUC((0, last)) for des-CIC on Day 14 was 213 ng.h/L and 112.3 ng.h/L for CIC-HFA 282 mug and 148 mug respectively. Mean serum cortisol (AUC(0-24h)) was similar for CIC-HFA 282 mug (178 mug.h/dL), CIC-HFA 148 mug (169 mug.h/dL), and placebo (174 mug.h/dL) on Day 14. The overall incidence of AEs was low and headache and epistaxis were the most common individual AEs reported. In this study, systemic exposure of des-CIC was low and similar in healthy subjects and subjects with PAR with no evidence of clinically relevant accumulation over the 14 day treatment period in either treatment group. Both doses of CIC-HFA were well tolerated without significant effect on cortisol levels.