|
 |
|
|||||||
|
|||||||||
Copyright ©ERS Journals Ltd 2001
Comparative efficacy and safety of mometasone furoate dry powder inhaler and budesonide Turbuhaler®
AstraZeneca R&D, S-221 87, Lund, Sweden
To the Editor:
Bousquet et al. 1 recently compared the efficacy and safety of mometasone furoate dry powder inhaler (MF DPI) and budesonide DPI (Turbuhaler®) for the treatment of moderate persistent asthma. They concluded that lower doses of MF DPI appeared to be more effective than a clinically recommended dose of budesonide DPI, while providing a comparable degree of safety.
For several reasons we do not agree with this conclusion. Experiences gained during the last decade have taught us that the greatest amount of care must be taken in the design of studies where the relative efficacy of inhaled steroids are to be investigated. Not least has it repeatedly been seen that the dose-response curves for these drugs on most antiasthma variables are very flat, which means that traditional dose-response studies are acceptable for comparisons of relative efficacy only if several doses are selected over a wide dose range 2. For budesonide, several studies have shown that a four-fold difference in dose may be necessary for ensuring statistically significant dose-differences 3, 4. In the study by Bousquet et al. 1 only one dose of budesonide Turbuhaler® (800 µg·day–1) was compared to three doses of MF DPI (200, 400 and 800 µg·day–1). The budesonide dose was as high as the highest dose of MF, so no information of what a lower dose of budesonide could have achieved in this patient population could be obtained. The lack of multiple doses of budesonide also turned out to be less ideal as the 800 µg dose of MF did not show any improvement over the 400 µg dose. Thus, for MF DPI also, a dose-response curve could not be constructed. Overall, the design chosen cannot prove any relative efficacy ratio between the two drugs.
It is also noticeable that one-third of the patients were already treated with similar doses of budesonide (mean doses 663 µg) when entering the study and for these patients a further improvement on 800 µg could hardly be expected. Patient expectations regarding treatment benefit would thus be nonexistent in this group as compared to other patients given the new inhaler. Also, one would have anticipated a more thorough compliance check, given the delicacy in comparing a new but similar inhaled steroid DPI treatment with an established one.
The most serious flaw is of course that the study was not blinded to the patients and that no double dummy technique was used. This might be difficult to obtain in dose-response studies, but alternative designs are available; in a double-blind study in asthmatic children utilizing dose-reduction of budesonide Turbuhaler® and fluticasone Diskhaler® every 5 weeks, minimal effective doses of the two preparations could be calculated 5. The study showed that there was no significant difference in clinical efficacy between the two preparations at similar doses. This result should be kept in mind as there have been claims that mometasone DPI and fluticasone Diskhaler® are comparable in efficacy 6.
The MF DPI seems to have been developed with Turbuhaler® as a close prototype. It differs, however, in some crucial dose-activating characteristics, e.g. the turning of the cap activates the dose-metering unit. More importantly, the MF DPI is labelled in delivered doses, whereas budesonide Turbuhaler® is labelled in metered doses. Thus, the 800 µg mometasone DPI dose that was used in the study by Bousquet et al. 1 was not compared with an identical dose of budesonide, but rather 560 µg, these are the doses that are delivered from the respective inhalers. This difference between the two preparations was not stated in the article, but may contribute to any claim regarding higher potency for the MF DPI versus other inhaled formulations.
Regarding the safety characteristics of mometasone furoate dry powder inhaler, the authors claim that both drugs provide a comparable degree of safety based on the lack of effect on the hypothalamic-pituitary-adrenal axis. However, these results are what would be expected given the low sensitivity of morning cortisol assessment to detect differences between treatment regimens 2. In the present study, this is evidenced by the same cortisol suppression following treatment with the lowest mometasone furoate dry powder inhaler dose (200 µg·day–1) as at baseline, where patients were given 400–800 µg·day–1 of other inhaled steroids. It still remains to be proven if the low systemic availability, claimed after inhalation of mometasone furoate 7, can be translated into low systemic effects, or if any pharmacologically active metabolite might explain the hypothalamic-pituitary-adrenal effects seen after inhaled doses of mometasone furoate 8, 9.
References
- Bousquet J, D'Urzo A, Hebert J, et al. Comparison of the efficacy and safety of mometasone furoate dry powder inhaler to budesonide Turbuhaler. Eur Respir J 2000;16:808–816.[Abstract]
- Boulet LP, Cockcroft DW, Toogood J, Lacasse Y, Baskerville J, Hargreave FE. Comparative assessment of safety and efficacy of inhaled corticosteroids: Report of a Committee of the Canadian Thoracic Society. Eur Respir J 1998;11:1194–1210.[Medline] [Order article via Infotrieve]
- Busse WW, Chervinsky P, Condemi J, et al. Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma. J Allergy Clin Immunol 1998;101:457–463.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
- Pauwels RA, Löfdahl CG, Postma DS, et al. Effect ofinhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997;337:1405–1411.
[Abstract/Free Full Text] - Agertoft L, Pedersen S. A randomized, double-blind dose reduction study to compare the minimal effective dose of budesonide Turbuhaler and fluticasone propionate Diskhaler. J Allergy Clin Immunol 1997;99:773–780.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
- O'Connor BJ, Bonnaud G, Luna JM, Sanchez-Borges M, Lutsky BN. Comparison of mometasone furoate (MF) administered by dry powder inhaler (DPI) with fluticasone propionate (FP) administered by Diskhaler in patients with moderate persistent asthma. Eur Respir J 1999;14:Suppl. 30197s.
- Affrime MB, Cuss F, Padhi D, et al. Bioavailability and metabolism of mometasone furoate following administration by metered-dose and dry-powder inhalers in healthy human volunteers. J Clin Pharmacol 2000;40:1227–1236.[Abstract]
- Affrime MB, Kosoglou T, Thonoor CM, Flannery BE, Herron JM. Mometasone furoate has minimal effects on the hypothalamic-pituitary-adrenal axis when delivered at high doses. Chest 2000;118:1538–1546.
[Abstract/Free Full Text] - Lipworth BJ, Jackson CM. Safety of inhaled and intranasal corticosteroids–Lessons for the new millenium. Drug Safety 2000;23:11–33.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |