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
Study objectives: Mometasone furoate dry powder inhaler (MF-DPI) [400 ␮g] 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 ␮g qd, on the HPA axis was compared to that of beclomethasone dipropionate
(BDP) using hydrofluoroalkane (HFA) and chlorofluorocarbon (CFC) propellants via metereddose inhalers (MDIs) twice daily.
Design and interventions: This randomized, third-party blind, parallel-group study compared the
effects of MF-DPI 400 ␮g one puff qd in the morning (n ⴝ 18), HFA-BDP 200 ␮g two puffs MDI
bid (n ⴝ 18), and CFC-BDP 400 ␮g two puffs MDI bid (n ⴝ 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 ⴝ 0.024) or the CFC-BDP
(p ⴝ 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 ␮g qd was associated with a
significantly lesser decrease in the serum cortisol concentrations AUC0 –24 compared with
HFA-BDP 200 ␮g MDI or CFC-BDP 400 ␮g MDI bid.
(CHEST 2005; 128:70 –77)
Key words: asthma, beclomethasone dipropionate; corticosteroid; hypothalamo-hypophyseal system; mometasone
furoate
Abbreviations: ANOVA ⫽ analysis of variance; AUC0 –24 ⫽ area under the 24-h serum cortisol concentrations curve;
BDP ⫽ beclomethasone dipropionate; CFC ⫽ chlorofluorocarbon; HFA ⫽ hydrofluoroalkane; HPA ⫽ hypothalamicpituitary-adrenal; ICS ⫽ inhaled corticosteroid; MF-DPI ⫽ mometasone furoate dry powder inhaler; PEF ⫽ peak
expiratory flow; UFC ⫽ urinary free cortisol
corticosteroids (ICSs) are recommended
I bynhaled
the Global Initiative for Asthma guidelines as
1
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
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Clinical Investigations
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 (MFDPI) is an ICS that has been shown to be effective
and well tolerated in treating subjects with mild-tomoderate10 and severe persistent asthma.11 Treatment with MF-DPI at doses up to 1,200 ␮g 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 ␮g 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
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
ⱖ 6 months and a FEV1 of ⱖ 80% predicted at screening after
withholding short- and long-acting ␤2-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 ⱖ 12% (or ⱖ 200 mL absolute volume)
increase in FEV1 after albuterol administration. A diurnal variation of ⱖ 20% in peak expiratory flow (PEF) rate or a positive
methacholine challenge test result (provocative concentration
causing a 20% fall in FEV1 ⱕ 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
*From the First Department of Pediatrics, Athens University
Medical School, Children’s Hospital “Agia Sophia,” Athens,
Greece; and Integrated Therapeutics Group, Kenilworth, NJ.
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.
Manuscript received September 22, 2004; revision accepted
December 2, 2005.
Reproduction of this article is prohibited without written permission
from the American College of Chest Physicians (www.chestjournal.
org/misc/reprints.shtml).
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@
med.uoa.gr
www.chestjournal.org
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 ␮g qd in the morning, HFA-BDP
via MDI 200 ␮g bid, or CFC-BDP via MDI 400 ␮g two puffs bid
for 14 days. ICS doses selected for this study were within the
range indicated for the treatment of patients with mild-tomoderate 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,
␤2-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 ␮g qd in the morning,
HFA-BDP via MDI 200 ␮g bid, or CFC-BDP via MDI 400 ␮g
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
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71
cortisol concentrations using a validated liquid chromatographytandem 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, ␣ ⫽ 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
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; CFCBDP, 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).
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 HFABDP 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).
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 CFCBDP 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 com-
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Clinical Investigations
Table 1—Baseline Demographic Characteristics*
Characteristics
Gender
Male
Female
Age, yr
18 to ⬍ 30
30 to ⬍ 65
Mean (SD)
Range
Race
White
Asian
Height, cm
Mean (SD)
Range
Weight, kg
Mean (SD)
Range
Body mass index
Mean (SD)
Range
FEV1 % predicted
Mean (SD)
Range
Duration of asthma, yr
Mean (SD)
Range
Morning PEF, L/min
Mean (SD)
Range
Evening PEF, L/min
Mean (SD)
Range
Serum cortisol concentration, nmol/L
Mean (SD)
Range
MF-DPI
HFA-BDP MDI
CFC-BDP MDI
p Value†
0.329
18 (100)
0 (0)
17 (94)
1 (6)
15 (88)
2 (12)
10 (56)
8 (44)
29.4 (8.2)
20–47
12 (67)
6 (33)
27.8 (8.6)
20–47
13 (77)
4 (24)
27.3 (9.5)
18–57
17 (94)
1 (6)
18 (100)
0 (0)
17 (100)
0 (0)
177.4 (6.8)
164–193
174.7 (6.7)
164–186
177.6 (7.3)
162–187
0.759
0.378
0.386
0.519
80.1 (10.3)
66–96
77.4 (9.8)
60–96
81.6 (13.0)
62–102
25.4 (2.7)
20.8–29.7
25.4 (3.1)
20.3–30.3
25.8 (3.1)
20.2–31.8
87.2 (7.1)
80–104
89.2 (6.8)
80–102
90.6 (8.1)
80–112
14.4 (14.0)
0.6–40.0
17.1 (9.6)
2.0–40.0
12.8 (7.8)
0.8–26.0
557.9 (58.1)
434.3–684.3
514.9 (86.9)
374.3–722.9
533.1 (91.7)
328.6–671.4
552.5 (62.1)
411.4–696.4
535.9 (78.8)
394.3–705.7
544.4 (105.1)
335.7–764.3
385.8 (119)
137–609
392.3 (134)
212–688
381.4 (158)
110–816
0.907
0.387
0.488
0.280
0.837
0.973
*Data are presented as No. (%) unless otherwise indicated.
†ANOVA model including treatment effect.
pared 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.
www.chestjournal.org
Discussion
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 ␮g bid vs
400 ␮g bid. This confirms previous findings by
Jackson and Lipworth13,14 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
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73
Table 2—Summary of Serum Cortisol AUC0 –24 at Baseline and at Day 14 in Subjects Receiving MF-DPI, HFA-BDP,
and CFC-BDP*
Pairwise Comparison
Variables
Baseline (nmol/L/24 h)
No.
Mean
SD
Median
Range
Day 14 (nmol/L/24 h)
No.
Mean
SD
Median
Range
Change from baseline, nmol/L/24 h
No.
Mean
SD
Median
Range
Percentage change from baseline, %
No.
Mean
SD
Median
Range
MF-DPI
HFA-BDP
CFC-BDP
95% CI
p Value
17
2,619
704
2,403
1,501–4,126
17
2,949
850
2,803
998.1–4,286
14
2,722
669
2,636
1,633–3,934
⫺ 188 – 848
⫺ 443 – 647
(HFA-BDP vs MF) 0.206
(CFC-BDP vs MF) 0.707
14
⫺ 875
948
⫺ 732
⫺ 2,635–612
⫺ 1,037 – ⫺ 78
⫺ 1,170 – ⫺ 160
(HFA-BDP vs MF) 0.024
(CFC-BDP vs MF) 0.011
14
⫺ 31
34
⫺ 24
⫺ 87–29
⫺ 51 – ⫺ 2
⫺ 50–2
(HFA-BDP vs MF) 0.035
(CFC-BDP vs MF) 0.065
17
2,410
631
2,375
1,140–3,578
17
⫺ 210
484
⫺ 310
⫺ 1,132–555
17
⫺7
19
⫺9
⫺ 34–25
17
2,182
1,061
2,504
⫺ 1,035–3,339
17
⫺ 767
627
⫺ 824
⫺ 2,033–472
17
⫺ 33
47
⫺ 23
⫺ 204–17
14
1,847
864
2,188
338.3–3,182
*CI ⫽ confidence interval.
that study,12 MF-DPI at doses from 200 ␮g bid to
1,200 ␮g 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 Others18,19 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,
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Clinical Investigations
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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75
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.
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 ␮g/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.23,24 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 ␮g 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 ␮g bid) and CFC-BDP (400 ␮g
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.
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