Dose-response for adrenal suppression with hydrofluoroalkane formulations of fluticasone propionate and beclomethasone dipropionate.
OBJECTIVE
With the recent introduction of hydrofluoroalkane (HFA) inhalers it is important to know the relative systemic safety profiles of inhaled corticosteroids. We therefore decided to compare systemic bioavailability of HFA-beclomethasone dipropionate (BDP) vs HFA-fluticasone propionate (FP).


METHODS
Sixteen healthy volunteers were randomised in placebo-controlled single blind cross-over fashion to receive 3 weeks with HFA-FP or HFA-BDP, given as 1 week cumulative doubling doses (nominal ex-valve) of 500, 1000 and 2000 microg day(-1), with a 1 week placebo run-in and wash-out. Overnight (22.00 h to 08.00 h) and early morning (08.00 h) urinary cortisol/creatinine excretion and 08.00 h serum cortisol were measured after each placebo and dosing period. All data were log-transformed to normalize their distribution.


RESULTS
Urine and serum cortisol were suppressed by 2000 microg FP and BDP vs placebo and by 1000 microg BDP vs placebo for urinary cortisol/creatinine (P < 0.05). Overnight urinary cortisol/creatinine ratio (the primary endpoint) was suppressed more by 1000 microg BDP vs 1000 microg FP (P < 0.05), amounting to a geometric mean fold difference (95% CI) of 1.64 (1.04-2.56). There were also more individual low values less than 3 nmol mmol(-1) with BDP than FP at 1000 microg: n = 8/16 vs n = 2/16 (P < 0.05).


CONCLUSIONS
There was dose-related suppression of corrected urinary cortisol/creatinine with the HFA formulations of BDP and FP. Suppression of overnight urinary cortisol/creatinine ratio was significantly greater with HFA-BDP than HFA-FP at 1000 microg. This suggests that the greater glucocorticoid potency of HFA-FP may be offset by the greater lung bioavailability of HFA-BDP.
Fowler
S J
SJ
Asthma and Allergy Research Group, Department of Clinical Pharmacology & Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY.
Orr
L C
LC
Wilson
A M
AM
Sims
E J
EJ
Lipworth
B J
BJ
D000280:Administration, Inhalation; D000311:Adrenal Glands / Q000187:drug effects*; D000328:Adult; D000730:Androstadienes / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001507:Beclomethasone / Q000008:administration & dosage* / Q000493:pharmacokinetics; D001682:Biological Availability; D003404:Creatinine / Q000652:urine; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D000068298:Fluticasone; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D006854:Hydrocortisone / Q000652:urine; D008168:Lung / Q000378:metabolism; D009330:Nebulizers and Vaporizers; D004364:Pharmaceutical Preparations; D016037:Single-Blind Method
D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D000893:Anti-Inflammatory Agents; D006845:Hydrocarbons, Fluorinated; D004364:Pharmaceutical Preparations; D003404:Creatinine; D000068298:Fluticasone; D001507:Beclomethasone; D006854:Hydrocortisone