Abstract
Aims
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 µg 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 µg FP and BDP vs placebo and by 1000 µg BDP vs placebo for urinary cortisol/creatinine (P < 0.05). Overnight urinary cortisol/creatinine ratio (the primary endpoint) was suppressed more by 1000 µg BDP vs 1000 µg 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 µg: 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 µg. This suggests that the greater glucocorticoid potency of HFA-FP may be offset by the greater lung bioavailability of HFA-BDP
Keywords: adrenal suppression, beclomethasone, dipropionate, fluticasone propionate, hydrofluoroalkane inhalers
Introduction
With the impending implementation of the Montreal Protocol and the introduction of chlorofluorocarbon (CFC) free inhalers confusion exists regarding equivalent doses of inhaled corticosteroids, and there are no clear guidelines as yet on this transition. For example, considering CFC formulations, fluticasone propionate (FP) exerts approximately two-fold greater systemic bioavailability (as adrenal suppression) compared with beclomethasone dipropionate (BDP) [1], and so one might extrapolate that the same relationship applies to their hydrofluoroalkane (HFA) formulations. However, the situation may be more complicated as CFC-FP has twice the systemic bioavailability of HFA-FP [2], whilst CFC-BDP has half the bioavailability of HFA-BDP [3]. We therefore decided to compare adrenal suppression between HFA-BDP (Beclazone, 250 µg per actuation, Norton Healthcare, Ireland) pressurized metered dose inhaler and HFA-FP (Flutide Forte, 250 µg per actuation, Glaxo-Wellcome, Germany) within their recommended nominal (ex-valve) dose range up to 2000 µg day−1.
Methods
Patients
Sixteen healthy volunteers, mean age 24.8 (s.e. 1.4) years were recruited from the adult population of Dundee. They were randomised in placebo-controlled single-blind crossover fashion to receive 3 weeks treatment with HFA-FP or HFA-BDP, given as 1 week cumulative doubling doses (nominal ex-valve) of 500, 1000 and 2000 µg day−1, with a 1 week placebo run-in and wash-out. Inhaler technique was reinforced at each visit, and patients were instructed to mouth rinse after each administration. The Tayside Committee on Medical Research Ethics gave ethical approval for the study, and all patients gave written informed consent.
Cortisol assays
Overnight (22.00 h to 08.00 h) and early morning (08.00 h) urinary cortisol/creatinine excretion was measured after each placebo and dosing period. Subjects also had blood for 08.00 h serum cortisol taken after lying supine for 30 min. A full description of the methods for fractionated urine collection and plasma and urine cortisol/creatinine assay is given elsewhere [4]. There was no cross reactivity with either FP or BDP.
Statistical analysis
The study was designed with 80% power to detect a 20% difference in overnight urinary cortisol/creatinine ratio (the primary endpoint) between treatments with the alpha error set at 0.05 (2-tailed). All data were log-transformed to normalize their distribution, followed by multifactorial analysis of variance (with subject, sequence and treatment as factors) and Bonferroni's multiple-range testing set at 95% confidence limits (two-tailed). The χ2 test compared individual low values for overnight urinary cortisol/creatinine excretion for each formulation.
Results
There were no significant differences between placebo values prior to HFA-FP and HFA-BDP for overnight and early morning urinary cortisol/creatinine excretion, and 08.00 h serum cortisol. There was significant (P < 0.05) suppression of overnight and early morning urinary cortisol/creatinine with 1000 µg day−1 of HFA-BDP and 2000 µg day−1 of both HFA-BDP and HFA-FP as compared with placebo (Table 1). This amounted to a geometric mean fold difference (95% CI) of 2.31 (1.41–3.76) for 2000 µg FP vs placebo, 2.65 (1.63–4.33) for 2000 µg BDP vs placebo, and 1.74 (1.11–2.73) for 1000 µg BDP vs placebo. At the 1000 µg dose for overnight urinary cortisol/creatinine there was a 1.64-fold (95% CI 1.04–2.56) greater mean suppression with HFA-BDP than HFA-FP as well as more individual low values (Figure 1) less than 3 nmol mmol−1 (8/16 vs 2/16 patients, P < 0.05). 08.00 h serum cortisol showed significant suppression with both drugs at 2000 µg day−1, amounting to a 1.84-fold (95% CI 1.08–3.14) difference for FP, and a 1.90-fold (1.11–3.25) difference for FP.
Table 1.
Geometric means (s.e. mean) are shown for overnight urinary cortisol/creatinine ratio (ONUC/C ratio), early morning urinary cortisol/creatinine ratio (EMUC/C ratio) and 08.00 h serum cortisol. Asterisk indicates significant (P < 0.05) difference from placebo; cross indicates significant difference between HFA-BDP and HFA-FP at 1000 µg.
| ONUC/C ratio (nmol mmol−1) | EMUC/C ratio (nmol mmol−1) | 08.00 h serum cortisol (nmol l−1) | |
|---|---|---|---|
| Pooled placebo | 6.13 (0.80) | 23.67 (3.66) | 437.3 (27.5) |
| HFA-FP | |||
| 500 µg | 5.94 (0.77) | 21.06 (3.52) | 407.7 (15.3) |
| 1000 µg | 5.76 (0.72) | 15.23 (2.24) | 398.5 (19.8) |
| 2000 µg | 2.66 (0.37)* | 8.52 (1.95)* | 239.7 (36.0)* |
| HFA-BDP | |||
| 500 µg | 5.39 (0.70) | 19.67 (3.28) | 423.2 (15.8) |
| 1000 µg | 3.52 (0.44)*† | 12.19 (1.80)* | 387.2 (19.3) |
| 2000 µg | 2.31 (0.28)* | 6.62 (1.54)* | 231.9 (34.8)* |
Figure 1.
Individual data for overnight urinary cortisol/creatinine ratio for each dose (500 µg, 1000 µg and 2000 µg) of HFA-beclomethasone and pooled placebo. Data points below the 3 nmol mmol−1 cut off line represent clinically significant cortisol supression.
Discussion
We have shown that there was dose-related adrenal suppression with HFA formulations of FP and BDP, whilst the latter exhibited greater suppression at 1000 µg day−1. This can be explained due to their relative systemic bioavailabilities and potencies as follows: a) HFA-FP has half the systemic bioavailability of CFC-FP [2]; b) CFC-FP has twice the systemic potency of CFC-BDP [1]; c) CFC-BDP has half the systemic bioavailability of HFA-BDP [3]. Thus, it may not be possible to directly extrapolate the relative systemic effects from CFC to HFA inhaled corticosteroid formulations.
We elected to measure fractionated moieties of overnight and early morning urinary cortisol/creatinine excretion as this has been shown to be as sensitive as full 24 h urine collection or an integrated 24 h serum cortisol profile [4, 5]. For outpatient studies the fractionated collections were easier to perform and compliance is better than the full 24 h urine collection. On inspecting the scatter plot for overnight urinary cortisol/creatinine it is evident that there is considerable interindividual variability in response to exogenous glucocorticoid administration, except there was more suppression at the high dose of both formulations. It was not surprising to find significant suppression with 08.00 h serum cortisol only at the highest dose of HFA-BDP and FP, as this is known to be less sensitive than measuring effects on fractionated urinary cortisol [4, 5].
We used doses of both formulations which are recommended for use in asthma up to 2000 µg daily. Given that the systemic bioavailability of the Norton HFA-BDP is twice that of CFC-BDP [3] it seems curious that patients are recommended to switch on a microgram equivalent basis. Indeed with another HFA-BDP formulation (Qvar, 3 m Healthcare) the recommendation is for a switch from CFC-BDP on a 0.5 µg equivalent basis, with a maximum dose of 800 µg day−1 based on good dose–response studies [6].
What are the potential clinical implications of our results? Both HFA-BDP and HFA-FP showed dose-related adrenal suppression, although we cannot evaluate the therapeutic ratio as we do not know their relative therapeutic efficacy. However assuming HFA-FP will exhibit at least the same degree of degree of antiasthmatic potency as HFA-BDP, then we could hypothesize that at least at high doses HFA-FP would appear to have a superior therapeutic ratio. Proper dose–response studies in asthmatic patients are required to investigate this hypothesis.
Acknowledgments
This study was funded by a University of Dundee Research Grant.
References
- 1.Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy. Arch Intern Med. 1999;159:941–955. doi: 10.1001/archinte.159.9.941. [DOI] [PubMed] [Google Scholar]
- 2.Wilson AM, Sims EJ, Orr LC, Lipworth BJ. Differences in lung bioavailability between different propellants for fluticasone propionate. Lancet. 1999;354:1357–1358. doi: 10.1016/S0140-6736(99)03581-3. [DOI] [PubMed] [Google Scholar]
- 3.Lipworth BJ, Jackson CM. Pharmacokinetics of chlorofluorocarbon and hydrofluoroalkane metered-dose inhaler formulations of beclomethasone dipropionate. Br J Clin Pharmacol. 1999;48:866–868. doi: 10.1046/j.1365-2125.1999.00098.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Wilson AM, Lipworth BJ. 24 hour and fractionated profiles of adrenocortical activity in asthmatic patients receiving inhaled and intranasal corticosteroids. Thorax. 1999;54:20–26. doi: 10.1136/thx.54.1.20. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.McIntyre HD, Mitchell CA, Bowler SD, Armstrong JG, Wooler JA, Cowley DM. Measuring the systemic effects of inhaled beclomethasone: timed morning urine collections compared with 24 hour specimens. Thorax. 1995;50:1280–1284. doi: 10.1136/thx.50.12.1280. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Busse WW, Brazinsky S, Jacobson K, et al. Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant. J Allergy Clin Immunol. 1999;104:1215–1222. doi: 10.1016/s0091-6749(99)70016-3. [DOI] [PubMed] [Google Scholar]