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Correspondence |

Adrenal Suppression With Mometasone Furoate/FormoterolAdrenal Suppression FREE TO VIEW

Brian J. Lipworth, MD
Author and Funding Information

From the Asthma and Allergy Research Group, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee.

Correspondence to: Brian J. Lipworth, MD, Asthma and Allergy Research Group, Medical Research Institute, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, Scotland; e-mail: b.j.lipworth@dundee.ac.uk


Financial/nonfinancial disclosures: The author has reported to CHEST the following conflicts of interest: Dr Lipworth has received unrestricted grants from Chiesi Ltd and Teva Pharmaceuticals Industries, Ltd; has acted as consultant to Cipla Limited, Chiesi Ltd, and Neo-inhalation Technologies Ltd; and has participated in Ad Boards for Chiesi Ltd and Teva Pharmaceuticals Industries as well as Teva Pharmaceuticals Industries Speaker Bureau.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;145(5):1175-1176. doi:10.1378/chest.14-0143
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To the Editor:

I read with interest the article by Kosoglou et al (December 2013)1 comparing the relative adrenal suppression of mometasone furoate/formoterol (MF/F) vs fluticasone propionate/salmeterol (FP/S) combination inhalers via metered-dose inhalers in patients with mild to moderate asthma. The geometric mean ratio for cortisol area under curve (AUC) comparing MF/F 400/10 μg bid (n = 15) vs FP/S 460/42 μg bid (n = 16) was 1.19 (90% CI, 1.01-1.40), which, although falling within predefined ± 30% equivalence limits (ie, corresponding to a ratio of 0.70-1.43), clearly represents a significant difference, as the lower CI exceeds unity, indicating that FP produces greater adrenal suppression than MF when used at higher doses. Indeed, the individual data in Figure 1 in their article1 appear to show more uniform adrenal suppression for FP/S 460/42 μg bid, with all but one subject exhibiting abnormal values less than unity for the ratio of cortisol AUC relative to baseline.

Although the geometric mean ratio for AUC cortisol for MF/F 200/10 μg bid (n = 13) was not significantly different from placebo (n = 16):0.92 (90% CI, 0.78-1.10), this could merely be due to type 2 error. Pointedly, there was no mention of any a priori power calculations. Moreover, for such pharmacodynamic end points it is more conventional to report 95% CI rather than 90% CI. On inspecting Figure 1,1 it appears that, for the ratio of cortisol AUC relative to baseline, there are only two of 16 individuals (13%) with abnormal values less than unity for placebo, vs seven of 13 (54%) for MF/F 200/10 μg bid. It is unclear if patients were washed out of their usual inhaled corticosteroid therapy prior to randomization, since they may already have exhibited a degree of adrenal suppression at baseline, which in turn would attenuate the ratio of subsequent suppression relative to baseline.

Since the lung bioavailability of MF/F is essentially determined by lung deposition, it would be informative to know the respective in vitro fine particle dose and particle size for each dose formulation of MF/F and how this compares to FP/S.2 It can be seen from pharmacokinetic data that the accumulation ratio between single and chronic dosing for the MF moiety is appreciable, being 2.64-fold and 4.46-fold at 200 μg and 400 μg doses, respectively, in keeping with its high degree of lipophilicity and large volume of distribution, which results in its known propensity for dose-related systemic adverse effects at steady state.3

The mean baseline FEV1 % predicted is not reported for each group either at baseline or while taking randomized treatments, which is important to know, because airway caliber will determine the degree of lung absorption of inhaled corticosteroid and, hence, its degree of systemic bioactivity4; for example, patients with an FEV1 of 60% predicted would be expected to absorb less MF than those with 90% predicted and, hence, produce less adrenal suppression. Furthermore, if the FEV1 % ended up being higher while taking formoterol or salmeterol, this might augment the relative degree of lung bioavailability from the MF or FP moieties, respectively. Finally, the authors omit to mention that using either of these combination inhalers through a spacer device would approximately double their relative lung bioavailability and associated degree of adrenal suppression.5 The data of Kosoglou et al1 serve to reinforce the importance of always stepping down to achieve the lowest possible maintenance dose of inhaled corticosteroid to achieve the least potential for long-term systemic exposure in a given individual patient.

References

Kosoglou T, Hubbell J, Cutler DL, et al. Hypothalamic-pituitary-adrenal axis effects of mometasone furoate/formoterol fumarate vs fluticasone propionate/salmeterol administered through metered-dose inhaler. Chest. 2013;144(6):1795-1802. [CrossRef] [PubMed]
 
Wilson AM, Sims EJ, Orr LC, Lipworth BJ. Differences in lung bioavailability between different propellants for fluticasone propionate. Lancet. 1999;354(9187):1357-1358. [CrossRef] [PubMed]
 
Fardon TC, Lee DKC, Haggart K, McFarlane LC, Lipworth BJ. Adrenal suppression with dry powder formulations of fluticasone propionate and mometasone furoate. Am J Respir Crit Care Med. 2004;170(9):960-966. [CrossRef] [PubMed]
 
Weiner P, Berar-Yanay N, Davidovich A, Magadle R. Nocturnal cortisol secretion in asthmatic patients after inhalation of fluticasone propionate. Chest. 1999;116(4):931-934. [CrossRef] [PubMed]
 
Nair A, McKinlay L, Williamson P, Short P, Burns P, Lipworth BJ. Comparative lung bioavailability of fluticasone/salmeterol via a breath-actuated spacer and conventional plastic spacers. Eur J Clin Pharmacol. 2011;67(4):355-363. [CrossRef] [PubMed]
 

Figures

Tables

References

Kosoglou T, Hubbell J, Cutler DL, et al. Hypothalamic-pituitary-adrenal axis effects of mometasone furoate/formoterol fumarate vs fluticasone propionate/salmeterol administered through metered-dose inhaler. Chest. 2013;144(6):1795-1802. [CrossRef] [PubMed]
 
Wilson AM, Sims EJ, Orr LC, Lipworth BJ. Differences in lung bioavailability between different propellants for fluticasone propionate. Lancet. 1999;354(9187):1357-1358. [CrossRef] [PubMed]
 
Fardon TC, Lee DKC, Haggart K, McFarlane LC, Lipworth BJ. Adrenal suppression with dry powder formulations of fluticasone propionate and mometasone furoate. Am J Respir Crit Care Med. 2004;170(9):960-966. [CrossRef] [PubMed]
 
Weiner P, Berar-Yanay N, Davidovich A, Magadle R. Nocturnal cortisol secretion in asthmatic patients after inhalation of fluticasone propionate. Chest. 1999;116(4):931-934. [CrossRef] [PubMed]
 
Nair A, McKinlay L, Williamson P, Short P, Burns P, Lipworth BJ. Comparative lung bioavailability of fluticasone/salmeterol via a breath-actuated spacer and conventional plastic spacers. Eur J Clin Pharmacol. 2011;67(4):355-363. [CrossRef] [PubMed]
 
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