title: Pharmacokinetic profile of beclomethasone dipropionate hydrofluoroalkane after intranasal administration versus oral inhalation in healthy subjects: results of a single-dose, randomized, open-label, 3-period crossover study.
abstract: BACKGROUND
  Beclomethasone dipropionate (BDP) is an anti-inflammatory corticosteroid that is rapidly metabolized to the pharmacologically active monoester, beclomethasone-17-monopropionate (17-BMP). Recently, a hydrofluoroalkane (HFA)-propelled nasal aerosol formulation of BDP was developed to treat allergic rhinitis. However, the pharmacokinetic profile of BDP HFA nasal aerosol has not been previously investigated.
  
  
  OBJECTIVE
  This study evaluated and compared the systemic levels of 17-BMP and BDP after a single dose of intranasally administered or orally inhaled BDP HFA in healthy subjects.
  
  
  METHODS
  In this single-center, randomized, open-label, 3-period crossover study, healthy subjects received single doses of intranasal BDP HFA (80 and 320 μg) and orally inhaled BDP HFA (320 μg). The primary pharmacokinetic parameters assessed were area under the concentration-time curve until the last measurable value (AUC(last)) and C(max) for 17-BMP. For AUC(last) and C(max), point estimates for treatment differences and CIs were calculated on the log scale and then exponentiated to provide estimates of the geometric mean ratios (GMRs) and associated CIs.
  
  
  RESULTS
  Thirty subjects were randomized to receive study medication (aged 18-45 years, 66.7% male). Mean plasma concentrations of 17-BMP after intranasal administration of BDP HFA (for both 80- and 320-μg doses) were substantially lower than that of orally inhaled BDP HFA (320 μg) across all time points. Mean AUC(last) values of 17-BMP for intranasal 80 μg, intranasal 320 μg, and orally inhaled 320 μg were 295.8, 1139.7, and 4140.3 pg·hr/mL, respectively. Mean C(max) values were 92.1, 262.7, and 1343.7 pg/mL, respectively. The GMR of AUC(last) for 17-BMP with intranasal BDP HFA 320 μg versus orally inhaled BDP HFA 320 μg was 0.275, indicating substantially lower systemic bioavailability with intranasal administration than with oral inhalation. Similarly, the GMR of AUC(last) for 17-BMP with intranasal BDP HFA 80 μg versus 320 μg was 0.260, suggesting approximate dose proportionality (4-fold difference). Pharmacokinetic results for BDP were similar to those seen for 17-BMP. All doses of intranasal and orally inhaled BDP HFA were well tolerated, and no treatment-related adverse events were reported.
  
  
  CONCLUSIONS
  The results of this study suggest that 80 and 320 μg BDP HFA nasal aerosols have substantially lower systemic bioavailability than 320 μg orally inhaled BDP HFA in healthy subjects. All treatments were well tolerated. ClinicalTrials.gov identifier: NCT01537692.
authors.affiliation: Sylvana Research Associates, San Antonio, TX 78229, USA. pratner@sylvanaresearch.com
authors.forename: Paul H
authors.initials: PH
authors.lastname: Ratner
authors.forename: Amy
authors.initials: A
authors.lastname: Melchior
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Dunbar
authors.forename: Sudeesh K
authors.initials: SK
authors.lastname: Tantry
authors.forename: Paul M
authors.initials: PM
authors.lastname: Dorinsky
mesh_terms: D000280:Administration, Inhalation; D000281:Administration, Intranasal; D000328:Adult; D019540:Area Under Curve; D001507:Beclomethasone / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008297:Male; D012016:Reference Values
chemical_list: D001507:Beclomethasone