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(Chest. 2005;128:70-77.)
© 2005 American College of Chest Physicians

Effects of Mometasone Furoate Dry Powder Inhaler and Beclomethasone Dipropionate Hydrofluoroalkane and Chlorofluorocarbon on the Hypothalamic-Pituitary-Adrenal Axis in Asthmatic Subjects*

George P. Chrousos, MD; Lisa Ghaly, PharmD; Arthur Shedden, MD, MBA; Domenic G. Iezzoni, MD and Alan G. Harris, MD, PhD

* From the First Department of Pediatrics, Athens University Medical School, Children’s Hospital "Agia Sophia," Athens, Greece; and Integrated Therapeutics Group, Kenilworth, NJ.

Correspondence to: George P. Chrousos, MD, First Department of Pediatrics, Athens University Medical School, Children’s Hospital "Agia Sophia," 11527 Athens, Greece; e-mail: chrousge{at}med.uoa.gr


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Mometasone furoate dry powder inhaler (MF-DPI) [400 µg] is an inhaled corticosteroid (ICS) that is effective in the treatment of asthma. MF-DPI has a low potential for suppression of the hypothalamic-pituitary-adrenal (HPA) axis at its clinical dose. The effect of MF-DPI, 400 µg qd, on the HPA axis was compared to that of beclomethasone dipropionate (BDP) using hydrofluoroalkane (HFA) and chlorofluorocarbon (CFC) propellants via metered-dose inhalers (MDIs) twice daily.

Design and interventions: This randomized, third-party blind, parallel-group study compared the effects of MF-DPI 400 µg one puff qd in the morning (n = 18), HFA-BDP 200 µg two puffs MDI bid (n = 18), and CFC-BDP 400 µg two puffs MDI bid (n = 17) for 14 days on the area under the 24-h serum cortisol concentrations curve (AUC0–24) and on total 24-h urinary free cortisol excretion in mild asthmatic subjects. Effects on morning/evening peak expiratory flow (PEF) and on inhaled albuterol use were also assessed. Adverse events that occurred during or ≥ 30 days after the study were recorded.

Results: The mean decrease from baseline in the serum cortisol concentrations AUC0–24 in the MF-DPI group was significantly less than in either the HFA-BDP (p = 0.024) or the CFC-BDP (p = 0.011) groups. Decreases in serum cortisol concentrations AUC0–24 in the two BDP groups did not differ from one another. The MF-DPI group trended toward higher morning and evening PEF than either BDP group. Treatment-associated adverse events were reported by seven subjects in the MF-DPI group, vs one subject in the HFA-BDP and three subjects in the CFC-BDP groups; these were mild, and no subject discontinued treatment due to an adverse event.

Conclusions: Fourteen days of treatment with MF-DPI 400 µg qd was associated with a significantly lesser decrease in the serum cortisol concentrations AUC0–24 compared with HFA-BDP 200 µg MDI or CFC-BDP 400 µg MDI bid.

Key Words: asthma, beclomethasone dipropionate • corticosteroid • hypothalamo-hypophyseal system • mometasone furoate


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Inhaled corticosteroids (ICSs) are recommended by the Global Initiative for Asthma guidelines1 as controller therapy for patients with persistent asthma. While ICSs improve asthma control in terms of decreased airway inflammation,2 less symptoms, fewer exacerbations,3 and improved quality of life,4 side effects can occur.5 Among these is impairment of the hypothalamic-pituitary-adrenal (HPA) axis, a finding manifested as suppression of cortisol secretion.5 HPA axis suppression occurs most commonly in association with long-term use of high-dose ICSs; however, suppression of the HPA axis can occur also with low-dose treatment.6 The potency of the ICS, the propellant or delivery device used, and the use of a spacing chamber7 may impact the systemic bioavailability of the ICS dose.8

Many studies have compared the effects of ICSs on the HPA axis, but not all have employed reliable measures. Among the laboratory tests used to assess the biochemical suppressive effect on the HPA axis, measurement of 24-h sequential serum cortisol concentrations is considered a discriminating, definitive test of basal HPA-axis function.9

Mometasone furoate dry powder inhaler (MF-DPI) is an ICS that has been shown to be effective and well tolerated in treating subjects with mild-to-moderate10 and severe persistent asthma.11 Treatment with MF-DPI at doses up to 1,200 µg qd for 28 days has shown minimal impacts on serum cortisol concentrations area under the 24-h serum cortisol concentrations curve (AUC0–24) and adrenal response to a low-dose cosyntropin test compared with placebo.12 In this study, we compared the effects of treatment with MF-DPI 400 µg qd on serum cortisol concentrations AUC0–24h and 24-h urinary free cortisol (UFC) excretion to that of beclomethasone dipropionate (BDP) delivered via metered-dose inhaler (MDI) with hydrofluoroalkane (HFA) and with chlorofluorocarbon (CFC) propellants twice daily in subjects with mild asthma.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Male and female subjects with mild asthma 18 to 65 years old were eligible for the study. All subjects had a history of asthma for ≥ 6 months and a FEV1 of ≥ 80% predicted at screening after withholding short- and long-acting ß2-receptor agonist treatment for 6 h and 48 h, respectively. At screening or within the previous 12 months, subjects had to demonstrate reversibility of airflow obstruction, defined as a ≥ 12% (or ≥ 200 mL absolute volume) increase in FEV1 after albuterol administration. A diurnal variation of ≥ 20% in peak expiratory flow (PEF) rate or a positive methacholine challenge test result (provocative concentration causing a 20% fall in FEV1 ≤ 8 mg/mL) were also accepted as evidence of airflow reversibility.

Subjects had normal morning serum cortisol concentrations at screening and were nonsmokers for > 3 months before the screening period. Physical examination and laboratory tests at screening were within normal limits or clinically acceptable to the investigator. All female subjects of childbearing age had to use an acceptable, nonhormonal method of birth control and had negative urinary pregnancy test results during the study.

Subjects were ineligible if they had used any investigational drug within 30 days prior to baseline, required daily or alternate day oral corticosteroid treatment for > 14 days during the 6 months immediately prior to screening, or required a course of systemic corticosteroids within the month prior to screening. Subjects were also excluded if they had an asthma-related hospital admission within the previous 3 months or more than once within the previous 6 months, or if they had required ventilator support for respiratory failure secondary to their asthma within the previous 5 years.

Subjects who were allergic to or had an idiosyncratic reaction to corticosteroids were excluded, and subjects with any significant physical or mental illness that could interfere with the study evaluations or affect subject safety could be excluded by the investigator. The study was approved by an independent ethics committee. All subjects provided written informed consent, and the study was conducted under the terms of the Declaration of Helsinki.

Study Design
This was a randomized, single-center, parallel-group study performed in adult ambulatory subjects with mild asthma. The study consisted of four visits: visit 1/screening (days – 21 to – 7), visit 2/baseline (days – 2 to 1), visit 3 (day 7), and visit 4 (days 14 to 16). Eligible subjects were randomized at baseline in a 1:1:1 ratio to receive MF-DPI 400 µg qd in the morning, HFA-BDP via MDI 200 µg bid, or CFC-BDP via MDI 400 µg two puffs bid for 14 days. ICS doses selected for this study were within the range indicated for the treatment of patients with mild-to-moderate asthma according to the prescribing information for each compound. This was a third-party blind study, in that the designated dispenser, who was not involved with the evaluations of the subject, dispensed the study medications. During the study, subjects were confined to the study center overnight on days – 2 and – 1 (visit 2) and days 14 and 15 (visit 4) to standardize the collection of 24-h serum and urine samples, and meal intake and fasting periods. Long-acting bronchodilators, ß2-adrenergic receptor blockers, corticosteroids, cromolyns, leukotriene modifiers, ipratropium bromide, and oral contraceptives were prohibited during the study.

Study Objectives
The primary objective was to evaluate the change from baseline in the serum cortisol concentration curves AUC0–24h after 14 days of treatment with MF-DPI 400 µg qd in the morning, HFA-BDP via MDI 200 µg bid, or CFC-BDP via MDI 400 µg bid. Secondary objectives included the changes from baseline in morning and evening PEF, the use of rescue albuterol, and changes from baseline in UFC excretion. All adverse events that occurred during the study were recorded and rated according to their severity and relationship to study treatment.

Tests
Serum cortisol at screening was measured using a chemiluminescent immunoassay (Immulite 2000; Diagnostic Products Corporation; glyn Rhonwy, UK). At baseline (visit 2) and after 2 weeks of treatment (visit 4), subjects underwent 24-h sequential measurements of serum cortisol concentrations. Blood samples were taken at 11 PM, 2 AM, 4 AM, 6 AM, 7 AM, 8 AM, 9 AM, 10 AM, and at 12 noon, 4 PM, 8 PM, and 11 PM, and were analyzed for cortisol concentrations using a validated liquid chromatography-tandem mass spectrometry procedure. Cumulative twenty-four–hour collections of urine for UFC excretion were performed at visits 2 and 4 and were analyzed for UFC with a validated liquid chromatography-tandem mass spectrometry system. Urine creatinine concentrations were measured, and total 24-h urine creatinine excretions were calculated. Beginning with the screening visit, subjects measured their PEF (Personal Best; Respironics; Murrysville, PA) morning and evening in triplicate and recorded the highest result in a study diary. Subjects also recorded in study diaries the number of puffs of albuterol required per 24-h period.

Statistical Methods
A sample size of 16 subjects per treatment group provided an 80% power to detect an absolute difference of 20% in the serum cortisol concentrations AUC0–24h between any two treatment arms (two-sided testing, {alpha} = 0.05). The mean change in serum cortisol concentration AUC0–24h at day 14 from baseline was analyzed with a one-way analysis of variance (ANOVA) model containing the treatment effect. Pairwise comparisons for this measure were performed for MF-DPI vs each BDP group, and between the two BDP groups, and 95% confidence intervals were calculated for each pairwise difference. The changes from baseline at day 14 in UFC excretion and PEF were analyzed with a one-way ANOVA model, while daily albuterol use was analyzed with an analysis of covariance model with baseline as the covariate. UFC excretion results in subjects with complete urine collections (within 10% variation in total urinary creatinine excretion between the two 24-h collection periods) were reported as a separate group. Adverse events and vital signs were evaluated for the safety population.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Demographics
A total of 53 subjects were enrolled and randomized to receive MF-DPI (n = 18), HFA-BDP (n = 18), or CFC-BDP (n = 17). Four subjects were discontinued from the study due to protocol ineligibility (MF-DPI, n = 1; HFA-BDP, n = 1; CFC-BDP, n = 2). Five subjects were excluded from the per protocol population; one subject in the MF-DPI group had a low serum cortisol at screening, while three subjects were excluded for using oral contraceptives (HFA-BDP, n = 1; CFC-BDP, n = 2) and one subject was excluded due to use of salmeterol (CFC-BDP, n = 1). No significant differences existed between the groups at baseline in terms of demographics, asthma severity profiles, or serum cortisol concentrations AUC0–24h (Table 1 ).


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  		Table 1. Baseline Demographic Characteristics*

 
Serum Cortisol Concentrations AUC0–24h
There were no significant differences in baseline serum cortisol concentrations AUC0–24 among the three groups (Table 2 ). Figure 1 shows the serum cortisol concentrations AUC0–24 curves at baseline and after 14 days of treatment in the MF-DPI, HFA-BDP, and CFC-BDP groups. The HFA-BDP and CFC-BDP groups showed significant decreases in the serum cortisol concentrations AUC0–24 compared with the MF-DPI group (Table 2, Fig 2 ). In the HFA-BDP group, the mean serum cortisol concentrations AUC0–24 fell from 2,949 nmol/L/24 h at baseline to 2,182 nmol/L 24 h at day 14 (decrease of 767 nmol/L). In the CFC-BDP group, the decrease from baseline in serum cortisol concentrations AUC0–24 was 875 nmol/L 24 h, falling from 2,722 nmol/L 24 h at baseline to 1,847 nmol/L 24 h on day 14 (Table 2). In the MF-DPI group, serum cortisol concentrations AUC0–24 changes were of lesser magnitude than in either of the BDP groups, falling from 2,619 nmol/L/24 h at baseline to 2,410 nmol/L 24 h at day 14, which represents a decrease of 210 nmol/L/24 h. Decreases in serum cortisol concentrations AUC0–24 were significantly greater in the HFA-BDP group (p = 0.024) and the CFC-BDP group (p = 0.011), compared with the MF-DPI group. The median percentage decreases in serum cortisol concentrations AUC0–24 were 9% with MF-DPI, 23% with HFA-BDP, and 24% with CFC-BDP (Fig 2).


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  		Table 2. Summary of Serum Cortisol AUC0–24 at Baseline and at Day 14 in Subjects Receiving MF-DPI, HFA-BDP, and CFC-BDP*

 


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  		Figure 1. Twenty-four–hour serum cortisol concentration curves in subjects at baseline and following 14 days of treatment with (top) MF-DPI (n = 17), (middle) HFA-BDP (n = 17), and (bottom) CFC-BDP (n = 14).

 


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  		Figure 2. Mean baseline, day 14, and mean change (median percentage in parenthesis) from baseline in AUC0–24 h serum cortisol in MF-DPI, HFA-BDP, and CFC-BDP groups. Changes from baseline, shown as values below the zero line, were significantly greater for both BDP formulations compared with MF-DPI. *p = 0.024 MF-DPI vs HFA-BDP; **p = 0.011 MF-DPI vs CFC-BDP.

 
Twenty-Four–Hour UFC Excretion
All three treatment groups demonstrated decreases in 24-h UFC excretion; the decreases in the two BDP groups were greater than that seen in the MF-DPI group. At baseline, mean 24-h UFC excretions were 70.8 nmol/L/24 h, 66.2 nmol/L/24 h, and 53.0 nmol/L/24 h in the MF-DPI, HFA-BDP, and CFC-BDP groups, respectively (p = not significant). The mean decrease in 24-h UFC excretion of 8.2 nmol/L/24 h (9.6%) with MF-DPI was lower than the decreases that occurred with HFA-BDP (27.9 nmol/L/24 h; 34.3%; p = 0.047) and CFC-BDP (18.0 nmol/L/24 h; 33.4%; p = 0.073). In the subset of subjects in whom day – 2/day 1 and day 14/day 15 24-h urine creatinine excretion were within 10% of each other (indicative of comparable 24-h urine collections for both days), the mean percentage decrease from baseline in 24-h UFC was 9.6% (– 5.9 nmol/L/24 h) in the MF-DPI group (n = 6), compared with 43.1% (– 34.8 nmol/L/24 h) in the HFA-BDP group (n = 7), and 30.0% in the CFC-BDP group (n = 7) [– 19.1 nmol/L/24 h].

PEF and Albuterol Use
PEF (liters per minute) was higher in the MF-DPI group at the end of the study than in either BDP group. The mean improvements in PEF were as follows: MF-DPI, 35 L/min (morning) and 41 L/min (evening); HFA-BDP, 20 L/min (morning) and 17 L/min (evening); and CFC-BDP, 21 L/min (morning) and 17 L/min (evening). The trends toward greater improvements in PEF with MF-DPI compared with the BDP groups were not statistically significant. No differences in daily albuterol use were noted among the study groups.

Safety
No serious adverse event occurred, and no subject discontinued due to an adverse event. Seven subjects in the MF-DPI group reported treatment-related adverse events, compared with one subject in the HFA-BDP group (p = 0.028), and three subjects in the CFC-BDP group. All treatment-related adverse events were mild or moderate in severity. The treatment-related adverse events in the MF-DPI group were dry throat (n = 3), sore throat (n = 2), dyspnea (n = 1), headache (n = 1), dizziness (n = 1), and fatigue (n = 1). There was one report of throat irritation in the HFA-BDP group, and dysphonia (n = 2), dyspepsia (n = 1), and dry throat (n = 1) were reported in the CFC-BDP group.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study compared the effect of MF-DPI on the HPA axis with that of another commonly used ICS, BDP, in subjects with asthma. The results demonstrate that a similar magnitude of HPA-axis suppression occurred with BDP via HFA and CFC MDI, despite the differences in BDP doses: 200 µg bid vs 400 µg bid. This confirms previous findings by Jackson and Lipworth1314 indicating greater systemic bioavailability and enhanced cortisol suppression with the HFA formulation of BDP vs the CFC formulation. The median percentage reduction in the serum cortisol concentrations AUC0–24 of 23 to 24% with BDP was significantly greater than the 9% reduction seen with MF-DPI treatment. This low magnitude of cortisol secretory suppression seen with MF-DPI is in keeping with a previous 28-day study12 in subjects with mild-to-moderate asthma. In that study,12 MF-DPI at doses from 200 µg bid to 1,200 µg qd had no impact on dynamic cortisol secretion in response to low-dose cosyntropin, while the mean serum cortisol concentrations AUC0–24h was in the range of 82 to 107% of placebo.

The minor effect of MF-DPI treatment on serum cortisol concentrations AUC0–24h compared with BDP in the current study was reflected in the results of the 24-h UFC excretion. The mean decrease in 24-h UFC excretion of 9.6% (– 8.2 nmol/L/24 h) with MF-DPI was lower than the decreases seen with HFA-BDP (34.3%; – 27.9 nmol/L/24 h; p = 0.047) and CFC-BDP (33.4%; – 18.0 nmol/L/24 h; p = 0.073). The difference between the MF-DPI and BDP groups was maintained in the subpopulation with validated full 24-h urine samples (MF-DPI, – 9.6% [– 5.9 nmol/L/24 h]; HFA-BDP, – 43.1% [– 34.8 nmol/L/24 h]; and CFC-BDP, – 30.0% [– 19.1 nmol/L/24 h]). Subjects in the MF-DPI group had greater improvements from baseline in PEF measured morning (35 L/min) and evening (41 L/min), compared with BDP (morning, 20 to 21 L/min; evening, 17 L/min; p = not significant).

Various methodologies have been used to measure the impact of ICSs on the HPA axis, but not all are sufficiently sensitive to detect suppression of HPA-axis activity. Appropriate test selection is particularly important when attempting to compare the effects of ICSs on the HPA axis. Basal HPA-axis function is best assessed using timed serum or plasma cortisol sampling, with 12-h overnight (8 PM to 8 AM)15 and 24-h periods8 having been validated. Spot morning cortisol assessments are now recognized as being insensitive markers of HPA-axis suppression, and may miss as many as 15% of cases of documented hypoadrenalism.16 The results of the current study reinforce these doubts regarding the sensitivity of spot morning cortisol assessments. There were marked variabilities in the differences between baseline and posttreatment from 6 to 10 AM in all treatment groups (Fig 1), indicating that a single measurement is not reliable to capture accurately the relative effects of various ICSs on cortisol secretion. The use of timed UFC excretion to assess the impact of ICSs on the HPA axis has been reported to suffer from intrastudy variability,15 and appropriate assays must be used.17 Others1819 have found, however, that timed UFC collections are a sensitive measure of HPA suppression with ICSs, and we found that 24-h UFC excretion mirrored the results of serum cortisol concentration AUC0–24h closely, particularly when total timed urine collections are confirmed as comparable. For dynamic testing of adrenal reserve, the low-dose cosyntropin test is preferred to the previous high-dose test, as it is more sensitive, returns fewer false results, and correlates better with the insulin-tolerance test.20 We did not test adrenal reserve in this study, but, as noted above, previous work has shown that mometasone furoate had no impact on the low-dose cosyntropin test at doses of 400 to 1,200 µg/d.12

The lower impact of MF-DPI on HPA-axis function as compared to HFA-BDP and CFC-BDP may be attributable to the relatively low systemic bioavailability of MF-DPI and its delivery by the dry powder inhaler device. Mometasone furoate has a high glucocorticoid receptor affinity, which is 22 times the relative receptor affinity of dexamethasone. The bioavailability of inhaled mometasone furoate has been estimated to be of the order of only 1%, which is largely determined by extensive first-pass metabolism of any swallowed drug.21 Furthermore, as dry powder inhaler delivery of ICSs results in higher lung deposition than delivery via CFC and HFA propellants,22 it appears that subsequent entry of inhaled MF-DPI from the lung into the systemic circulation does not occur to a significant degree, perhaps due to elimination by hepatic metabolism. On a separate point, it has been shown that the systemic bioavailability of an ICS may depend on the severity of lung compromise, with asthmatic patients having lower systemic exposure to inhaled fluticasone propionate than healthy volunteers.2324 This underlines the importance of performing pharmacokinetic studies of ICSs at therapeutic doses in patients with asthma—as we did in this study—rather than simply extrapolating data from a healthy population.

In conclusion, this study demonstrates that in subjects with mild asthma, 14 days of treatment with MF-DPI 400 µg qd has a significantly lower effect on HPA-axis function as assessed by serum cortisol concentrations AUC0–24h and UFC, as compared with HFA-BDP (200 µg bid) and CFC-BDP (400 µg bid). Further studies would be useful to determine whether this benefit of MF-DPI over HFA-BDP and CFC-BDP in terms of HPA-axis function endures during long-term treatment of asthma in the clinical setting.


   Footnotes
 
Abbreviations: ANOVA = analysis of variance; AUC0–24 = area under the 24-h serum cortisol concentrations curve; BDP = beclomethasone dipropionate; CFC = chlorofluorocarbon; HFA = hydrofluoroalkane; HPA = hypothalamic-pituitary-adrenal; ICS = inhaled corticosteroid; MF-DPI = mometasone furoate dry powder inhaler; PEF = peak expiratory flow; UFC = urinary free cortisol

This study was performed at Simbec Research Ltd, Merthyr Tydfil, Cardiff, UK.

This study supported by Integrated Therapeutics Group, Inc., a subsidiary of Schering-Plough Corporation, Kenilworth, NJ.

Received for publication September 22, 2004. Accepted for publication December 2, 2005.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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C. Leach, P. LeSouef, G. P. Chrousos, L. Ghaly, D. Iezzoni, A. Shedden, and A. G. Harris
Mometasone and Beclomethasone Comparison Article Observations
Chest, May 1, 2006; 129(5): 1389 - 1391.
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