Once-Daily Evening Dosing of Mometasone Furoate Administered via a Dry Powder Inhaler Does Not Adversely Affect the Hypothalamic-Pituitary-Adrenal Axis

doi:10.1378/chest.09-0235

Chest

Volume 137, Issue 1, January 2010, Pages 115-121

https://doi.org/10.1378/chest.09-0235 Get rights and content

Background

Inhaled corticosteroids can suppress the hypothalamic-pituitary-adrenal (HPA) axis with long-term exposure. This study reports the effects of moderate-dose (400 μg) mometasone furoate administered via dry powder inhaler (MF-DPI) once daily in the evening on the HPA axis in adults with mild to moderate asthma.

Methods

In this randomized, investigator-blind, placebo-controlled trial, nonsmoking adults aged 18 to 50 years with mild-to-moderate asthma received once-daily MF-DPI 400 μg (2 × 200 μg/inhalation; treatment A), MF-DPI 400 μg (1 × 400 μg/inhalation; treatment B), or placebo (two inhalations, treatment C), delivered at approximately 8:00 pm, for 42 days. Primary end points were area under the serum cortisol concentration-vs-time curve over 24 h (AUC_0-24), 24-h urinary free cortisol (creatinine corrected) on day 42, maximum serum cortisol concentration (C_max), time to C_max (T_max), and 8:00 am serum cortisol concentration. This study was initiated April 16, 2001 and completed June 14, 2001.

Results

Serum cortisol AUC_0-24, C_max, and 24-h urinary free cortisol levels decreased with all treatments by day 42 with no significant differences between groups. For treatment B, the change in 8:00 am serum cortisol from baseline to day 42 was significantly less than placebo (P = .04), attributed to a large baseline difference between these treatments. A significant difference in T_max change from baseline by day 42 for treatment B compared with the other treatments (P = .019) was also attributed to significant baseline differences between groups. Actual values at day 42 for T_max and 8:00 am serum cortisol were not significantly different between treatment groups (P ≥ .275).

Conclusions

Once-evening moderate dosing (400 μg) MF-DPI does not suppress HPA axis function in adults with mild to moderate asthma.

Section snippets

Methods

This single-site study was a randomized, investigator-blind, parallel-group, placebo-controlled trial conducted in adults with mild-to-moderate asthma. Written informed consent was received from all eligible subjects, and the trial was conducted in accordance with the Good Clinical Practice guidelines. This study was initiated April 16, 2001 and completed June 14, 2001.

Subject Demographics and Baseline Characteristics

A total of 48 subjects were randomized to participate, and all subjects completed the 42-day study (Fig 1B). Subject demographics and baseline characteristics are summarized in Table 1. A total of 16 men and 32 women participated in the study with a mean age of 39.5 years. Treatment groups were comparable in terms of age, weight, height, and BMI. Reported FEV₁ at baseline was also comparable between treatment groups, ranging from 67.5% to 70.6%, and all subjects had a history of mild or

Discussion

We found that 42 days of treatment with MF-DPI 400 μg daily in the evening, delivered in either 2 × 200 or 1 × 400 μg dosing strategies, had no significant effect on HPA-axis activity. This study is unique because the effects of evening ICS dosing were investigated and found to have no significant effect on HPA-axis function. These findings are consistent with previous analyses of MF-DPI dosing regimens, including once-daily evening dosing of 200 μg, all of which reported nonsignificant effects

Conclusions

The results of this study support the systemic safety of MF-DPI 400 μg daily delivered in the evening. These results suggest that a once-evening dosing regimen of MF-DPI is safe and does not suppress HPA-axis function in adult patients with mild-to-moderate asthma.

Acknowledgments

Author contributions: Dr Kosoglou had full access to all the data and takes full responsibility for the integrity and accuracy of the data and manuscript.

Dr Kosoglou: contributed to the analysis and interpretation of the data, critically revised the manuscript for intellectual content, and approved the final version.

Dr Cutler: contributed to the analysis and interpretation of the data, critically revised the manuscript for intellectual content, and approved the final version.

Dr Staudinger:

References (0)

Cited by (9)

Impact of study design on the evaluation of inhaled and intranasal corticosteroids' effect on hypothalamic-pituitary-adrenal axis function
2014, Journal of Pharmaceutical Sciences
In part I of this review, an overview of the designs of hypothalamic–pituitary–adrenal (HPA) axis studies in the setting of inhaled corticosteroids (ICS) or intranasal corticosteroids (INS) use was discussed. Part II provides detailed discussion on the HPA axis evaluation results for each common ICS and INS, and how these results are possibly affected by the factors of study design. Significant adrenal suppression at conventional ICS/INS doses appears to be rare in clinical settings. The magnitude of cortisol suppression varies widely among different study designs. Factors potentially impacting this variability include: the choice of dose, dosing duration, assay sensitivity, statistical methodology, study population, and compliance. All of these factors have the potential to affect the extent of HPA axis effects detected and should be considered when designing or interpreting the results of a HPA axis study. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2963–2979, 2014
Hypothalamic-pituitary-adrenal axis effects of mometasone furoate/formoterol fumarate vs fluticasone propionate/salmeterol administered through metered-dose inhaler
2013, Chest
Citation Excerpt :
Taken together, these results suggest that low-dose MF/F MDI does not have demonstrable effects on plasma cortisol levels, whereas high-dose MF/F or FP/S MDI appeared to suppress plasma cortisol levels in adults with mild to moderate asthma, although these effects are not considered clinically significant. These results are consistent with those previously published for MF and FP administered as single-ingredient products through MDI.9,10 Over the years, a number of approaches have been used to assess HPA axis function, including the measurement of a single morning (8:00 am) cortisol value, a 24-h serum/plasma cortisol AUC, or 24-h urinary free cortisol excretion and the response to cosyntropin stimulation.9
The effects of mometasone furoate and fluticasone propionate on the hypothalamic-pituitary-adrenal axis were compared when administered from combination metered-dose inhaler (MDI) products.
In a randomized, open-label, placebo-controlled, parallel group study, 66 patients with mild to moderate asthma received one of the following four treatments bid through an MDI for 42 days: mometasone furoate/formoterol (MF/F) 200 μg/10 μg, MF/F 400 μg/10 μg, fluticasone propionate/salmeterol (FP/S) 460 μg/42 μg, or placebo. Plasma cortisol concentrations were measured over 24 h on days −1 (baseline) and 42. Geometric mean ratio (GMR) and 90% CI for mean change from baseline to day 42 in 24-h plasma cortisol area under the curve (AUC) were calculated for each treatment. If the 90% CI for the GMRs fell within 70% to 143%, treatments were deemed comparable.
Mean baseline cortisol AUCs were similar across groups. Mean cortisol effects (change from baseline) were similar for MF/F 400 μg/10 μg and FP/S 460 μg/42 μg (GMR, 119%; 90% CI, 101%-140%). Effects of MF/F 200 μg/10 μg on cortisol AUC were similar to placebo (GMR, 92%; 90% CI, 78%-110%), whereas MF/F 400 μg/10 μg and FP/S 460 μg/42 μg lowered cortisol AUC vs placebo (GMR, 78% [90% CI, 66%-92%] and 66% [90% CI 56%-78%], respectively). All treatments were generally well tolerated.
MF/F 400 μg/10 μg or FP/S 460 μg/42 μg bid through an MDI led to similar reductions from baseline in mean cortisol AUC (22% and 34% lower than placebo, respectively), whereas the effect of MF/F 200 μg/10 μg was similar to placebo.
Impact of study design on the evaluation of inhaled and intranasal corticosteroids' effect on Hypothalamic-Pituitary-Adrenal Axis Function, Part I: General overview of HPA Axis study design
2013, Journal of Pharmaceutical Sciences
Inhaled and intranasal corticosteroids (ICS and INS) are among the mainstays of the treatment for asthma and allergic rhinitis, respectively, and also carry the potential to suppress the hypothalamic-pituitary-adrenal (HPA) axis. Several important factors affect the interpretability of trials investigating the impact of ICS and INS on the HPA axis. This paper reviews 106 published clinical trials, peer-reviewed articles, and New Drug Application reviews of approved ICS and INS, using MEDLINE and Drugs@FDA database. The trials included in this review evaluated the potential impact on HPA axis function of eight approved single-ingredient ICS and INS (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone furoate, flucticasone propionate, mometasone furoate, and triamcinolone acetonide) and combination products containing these ingredients. The most commonly utilized design was blinded, placebo controlled, and short term (< 6 weeks) for adult trials and blinded, placebo controlled, and long term (≥ 6 weeks) for pediatric trials. Factors potentially affecting trial results include the choice of dose, dosing duration, assay sensitivity, statistical methodology, and the study population evaluated (patients or healthy volunteers). All of these factors have the potential to affect the level of adrenal suppression detected. In conclusion, to be informative, a HPA axis study should be well designed and carefully implemented to minimize variability in results and improve the overall interpretability of data obtained.
Efficacy and Safety Profile of Fluticasone Furoate Administered Once Daily in the Morning or Evening: A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled Trial in Adult and Adolescent Patients With Persistent Bronchial Asthma
2012, Clinical Therapeutics
Citation Excerpt :
Some efficacy benefits have been reported to be associated with evening dosing relative to morning.11,12 Morning dosing has been thought to minimize suppression of the hypothalamic-pituitary-adrenal (HPA) axis relative to dosing at other times.13 However, some more recent studies have not found HPA axis function to be adversely affected by evening dosing.11,12,14,15 The ICS fluticasone furoate (FF) is currently in development as a monotherapy for asthma and in combination with the long-acting β2 agonist vilanterol for asthma and chronic obstructive pulmonary disease.
Fluticasone furoate (FF) is an inhaled corticosteroid that is structurally and functionally distinct from fluticasone propionate and is under development as a once-daily therapy for asthma.
The objective of this study was to estimate the treatment differences (with 95% CI) in efficacy and safety profile between FF administered once daily in the morning and evening via Rotadisk Diskhaler (see text) in patients with persistent asthma. No hypothesis testing was performed for this comparison.
This was a randomized, double-blind, double-dummy, placebo-controlled, parallel-group study. Patients (ages 16−55 years; peak expiratory flow [PEF] 50%−90% predicted) were randomized to receive 1 of 3 doses of FF Rotadisk or placebo daily for 4 weeks. The sponsor, GlaxoSmithKline, designed the study and selected the study sites. The primary end point was change from baseline in daily trough (pretreatment, prebronchodilator) PEF during the treatment period with FF Rotadisk 100 μg once daily in the morning compared with 100 μg once daily in the evening. Other end points included change from baseline in forced expiratory volume in 1 second, asthma symptom score, adverse events (AEs), 24-hour urinary cortisol excretion, and FF pharmacokinetics.
Five hundred and seventy-five patients (mean age 36.6 years, 56.9% female) formed the intent-to-treat population and were randomly allocated to FF Rotadisk 100 μg once daily in the morning (n = 144), FF Rotadisk 100 μg once daily in the evening (n = 146), FF Rotadisk 250 μg once daily in the evening (n = 142), or placebo (n = 143). Of these patients, 526 (91.5%) completed the study. A smaller proportion of patients in the placebo group (86.7%) than in the active treatment groups completed the study. Mean difference in PEF change from baseline with FF Rotadisk 100 μg once daily in the morning relative to evening was +13.4 L/min (95% CI, 2.3−24.4). However, morning trough values might have been affected by higher placebo response after morning dosing (18.8 vs 8.8 L/min). Trough PEF improved relative to placebo (P ≤ 0.005), with little difference between FF Rotadisk 100 μg morning (19 L/min) and evening (16 L/min) dosing, as with other efficacy measures. Frequencies of all-cause AEs were similar with FF Rotadisk (32%–39%, 2 serious AEs) and placebo (37%, 1 serious AE). No serious AEs were deemed by the investigator to be related to study treatment. Twenty-four-hour urinary cortisol increased from baseline in all groups, but the increase was significantly lower with FF Rotadisk 250 μg group than placebo.
FF Rotadisk administered once daily in the morning or evening was well tolerated and associated with improvements in lung function and asthma symptoms compared with placebo. Improvements seen for FF Rotadisk 100 μg appear to be comparable for morning and evening dosing. Clinical.trials.gov NCT01499446.
Combination of mometasone furoate and oxymetazoline for the treatment of adenoid hypertrophy concomitant with allergic rhinitis: A randomized controlled trial
2017, Scientific Reports
Particle size and small airway effects of mometasone furoate delivered by dry powder inhaler
2013, Allergy and Asthma Proceedings

View all citing articles on Scopus

Funding/Support: This study was supported by Schering-Plough.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/site/misc/reprints.xhtml).

View full text

Chest

Original ResearchAsthmaOnce-Daily Evening Dosing of Mometasone Furoate Administered via a Dry Powder Inhaler Does Not Adversely Affect the Hypothalamic-Pituitary-Adrenal Axis

Background

Methods

Results

Conclusions

Section snippets

Methods

Subject Demographics and Baseline Characteristics

Discussion

Conclusions

Acknowledgments

Original Research
Asthma
Once-Daily Evening Dosing of Mometasone Furoate Administered via a Dry Powder Inhaler Does Not Adversely Affect the Hypothalamic-Pituitary-Adrenal Axis