Pharmacokinetics of ciclesonide and desisobutyryl ciclesonide after administration via aqueous nasal spray or hydrofluoroalkane nasal aerosol compared with orally inhaled ciclesonide: an open-label, single-dose, three-period crossover study in healthy volunteers

Abstract

Background: Ciclesonide, an intranasal corticosteroid, is administered as a prodrug and is converted to the active metabolite, desisobutyryl ciclesonide, in the upper and lower airways. Previous studies have assessed systemic exposure with the ciclesonide hydrofluoroalkane metered dose inhaler (CIC HFA-MDI) and the ciclesonide aqueous nasal spray (CIC-AQ) formulations. However, systemic exposure with ciclesonide HFA nasal aerosol (CIC-HFA) developed for the treatment of allergic rhinitis has not been investigated.

Objective: This study compared the systemic exposure of ciclesonide and desisobutyryl ciclesonide after administration of ciclesonide formulated as an aqueous nasal spray, an HFA nasal aerosol, or as an orally inhaled HFA-MDI.

Methods: Healthy adults (aged 18-60 years) were randomly assigned in an open-label, singledose, 3-period crossover design to CIC-AQ 300 microg, CIC-HFA 300 microg, or CIC HFA-MDI 320 microg. Serum samples were collected before study drug administration and at 5, 15, and 30 minutes and 1, 1.5, 2, 3, 4, 6, 8, 10, 12, 14, 18, 22, and 24 hours after dosing. The primary pharmacokinetic parameters were AUC(0-infinity) and C(max) of desisobutyryl ciclesonide. Adverse events were elicited by direct questioning of participants throughout the study.

Results: Thirty volunteers were randomly assigned. Most of the volunteers were male (63% [19/30]) and white (83% [25/30]); the mean age was 36 years and mean weight was 68 kg. Concentrations of desisobutyryl ciclesonide were quantifiable (lower limit of quantitation [LLOQ] = 10 ng/L) in the serum samples of only 5 volunteers (of 30) receiving CIC-AQ, and the highest C(max) value of desisobutyryl ciclesonide was 26.7 ng/L (mean C(max), 15.2 ng/L). The AUC(0-infinity) of desisobutyryl ciclesonide for CIC-AQ was below the LLOQ of the bioanalytic assay. Mean C(max) and AUC(0-infinity) of desisobutyryl ciclesonide were 59.1 ng/L and 397.5 ng . h/L, respectively, for CIC-HFA; and 586.2 ng/L and 2685.0 ng . h/L, respectively, for CIC HFA-MDI. Concentrations of the parent compound, ciclesonide, were below the LLOQ in serum samples after administration of CIC-AQ; they were detectable up to 2 hours after administration of CIC-HFA and up to 4 hours after administration of CIC HFA-MDI. Treatment-emergent adverse events occurred with a low frequency in all 3 treatment groups (30% [9/30] overall) and were mild in intensity as determined by the study investigator.

Conclusions: In this study, compared with that of CIC HFA-MDI, the systemic exposure of desisobutyryl ciclesonide was 10-fold lower after administration of CIC-HFA and at least 40-fold lower after administration of CIC-AQ. All treatments were well tolerated.

Trial registration: ClinicalTrials.gov NCT00458835.