Relative lung delivery of fluticasone propionate via large volume spacer or nebuliser in healthy volunteers.
OBJECTIVE
High-dose nebulised fluticasone propionate (FP) has been advocated for use in patients with severe persistent asthma. As there is complete first-pass inactivation of FP for the swallowed fraction, systemic absorption is due solely to its lung bioavailability. We wished to compare the relative lung delivery of FP, using adrenal suppression as a surrogate for the respirable dose, when administered via large volume spacer (FP-spacer) or nebuliser (FP-neb) in healthy adults.


METHODS
Fourteen healthy subjects, mean (SEM) age 29.4 +/- 2.6 years, were studied in a placebo-controlled, randomised study with three-way crossover design. Single nominal 2-mg doses of the following were given at 1700 hours in randomised sequence: a. FP-spacer: fluticasone pressurised metered dose inhaler (as Flixotide 250 microg ex-valve per actuation), eight puffs via a primed Volumatic 750-ml spacer. b. FP-neb: (as Flixotide Nebule 2 mg/2 ml) via Pari LC Plus nebuliser. c. Placebo nebuliser. Following each dose, measurements were made of corrected 0800-hours urinary cortisol/creatinine ratio (the primary outcome variable) and 0800-hours plasma cortisol.


RESULTS
Significant (P<0.05) suppression of both endpoints occurred only with FP-spacer, FP-neb being statistically no different from placebo. Geometric mean fold differences between FP-spacer and placebo were 9.8-fold [95% confidence interval (CI) 3.4, 28.8] for urinary cortisol/creatinine and 4.1-fold (95% CI 2.2, 7.5) for plasma cortisol. Comparing FP-spacer with FP-neb, these differences were 6.8-fold (95% CI 2.3, 20.0) for urinary cortisol/creatinine and 3.3-fold (95% CI 1.8, 6.0) for plasma cortisol.


CONCLUSIONS
For a 2-mg labelled nominal dose of fluticasone, the spacer produced about a sevenfold higher relative lung dose than the nebuliser. This suggests that a very little of the labelled nebulised dose is respirable. Other factors such as patient preference, cost and compliance will determine the inhaler device that is chosen.
Dempsey
O J
OJ
Department of Clinical Pharmacology and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Scotland, UK.
Humphreys
M
M
Coutie
W J
WJ
Lipworth
B J
BJ
D000280:Administration, Inhalation; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D015415:Biomarkers / Q000097:blood / Q000652:urine; D003404:Creatinine / Q000652:urine; D018592:Cross-Over Studies; D005260:Female; D000068298:Fluticasone; D006801:Humans; D006854:Hydrocortisone / Q000097:blood / Q000652:urine; D008168:Lung / Q000187:drug effects*; D008297:Male; D009330:Nebulizers and Vaporizers
D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D015415:Biomarkers; D003404:Creatinine; D000068298:Fluticasone; D006854:Hydrocortisone