Adrenal Suppression with Dry Powder Formulations ofFluticasone Propionate and Mometasone FuroateTom C. Fardon, Daniel K. C. Lee, Kay Haggart, Lesley C. McFarlane, and Brian J. Lipworth

Asthma and Allergy Research Group, Department of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee,Dundee, Scotland, United Kingdom

Mometasone furoate (MF) and fluticasone propionate (FP) are highpotency inhaled corticosteroids. The systemic bioavailability of MF isclaimed to be negligible, leading to a minimal potential for systemicadverse effects. We assessed the overnight urinary cortisol/creatinineas the primary outcome of adrenal suppression in 21 patients withpersistent asthma (mean FEV1 � 91%). Patients were randomized in acrossover fashion to receive 2 weekly consecutive doubling incrementaldoses of either FP Accuhaler (500, 1,000, and 2,000 �g/day) or MFTwisthaler (400, 800, and 1,600 �g/day). For the 21 per protocolcompleted patients, there was significant suppression of overnighturinary cortisol/creatinine with high and medium doses of bothdrugs—as geometric mean fold suppression (95% confidence inter-val) from baseline: FP 2,000 �g, 1.85 (1.21–2.82, p � 0.002); FP1,000 �g, 1.45 (1.07–1.96, p � 0.02); MF 1,600 �g, 1.92 (1.26–2.93,p � 0.001); and MF 800 �g, 1.39 (1.04–1.88, p � 0.02). For secondaryoutcomes of 8:00 A.M. plasma cortisol, serum osteocalcin, and earlymorning urinary cortisol/creatinine, there was significant suppres-sion with MF and FP at the highest dose. Our data refute the asser-tion that MF has negligible systemic bioavailability and a lowerpotential for systemic adverse effects compared with FP.

Keywords: adrenal suppression; asthma corticosteroids; fluticasone;mometasone

Inhaled corticosteroids (ICS) are the mainstay of treatment inpersistent asthma (1–5). The exact mechanism of action leadingto the beneficial effects of ICS in asthma is not fully understood;however, a key event is the binding of the glucocorticoid tothe cytosolic glucocorticoid receptor (3, 5). The glucocorticoidreceptor is present in a wide range of cells. Sustained elevationof plasma glucocorticoid levels stimulates these ubiquitous glu-cocorticoid receptors, leading to unwanted systemic side effectssuch as adrenal suppression, altered bone metabolism, and im-pairment of growth in children (5–9). Although the use of ICSin the long-term management of asthma is recommended, it isadvised that the lowest effective dose of ICS should be prescribedto minimize these systemic side effects (1). There are concernsthat even the currently advised levels of ICS can, in the longterm, lead to systemic side effects. This has driven efforts todevelop novel ICS moieties with improved therapeutic effectlocally in the lung, with minimized systemic side effects.

Mometasone furoate is a high-potency steroid currently li-censed in the United Kingdom as a powder-lactose mixtureadministered by breath actuated dry powder inhaler. It has beenshown to be highly effective in patients with mild-to-moderate

(Received in original form April 14, 2004; accepted in final form June 7, 2004)

Supported by a University of Dundee Research Grant.

Correspondence and reprint requests should be addressed to Brian J. Lipworth,M.D., F.R.C.P., F.A.C.A.A.I., Asthma and Allergy Research Group, Department ofMedicine and Therapeutics, Ninewells Hospital and Medical School, University ofDundee, Dundee, Scotland DD1 9SY, UK. E-mail: b.j.lipworth@dundee.ac.uk

This article has an online supplement, which is accessible from this issue’s tableof contents at www.atsjournals.org

Am J Respir Crit Care Med Vol 170. pp 960–966, 2004Originally Published in Press as DOI: 10.1164/rccm.200404-500OC on June 7, 2004Internet address: www.atsjournals.org

persistent asthma (10–12). In vitro studies have shown mometasonefuroate to have a binding affinity for the human glucocorticoidreceptor that is approximately 22 times that of dexamethasone(13), 7 times that of triamcinolone acetonide, 5 times that of bude-sonide, and 1.5 times that of fluticasone propionate (14). Datashow that mometasone furoate has a relative potency at theglucocorticoid receptor expressed as EC50 (the molar concentra-tion of an agonist which produces 50% of the maximum possibleresponse at the receptor) of 0.07 nmol/L with the respectivevalues for fluticasone propionate and budesonide of 0.32 and1.2 nmol/L (14). Furthermore, this rank order of potency hasbeen confirmed in terms of inhibition of histamine release fromprimed respiratory epithelial basophils in vitro (15), in termsof interleukin-5 release from TH-1 cells (16), and in terms ofinduction of eosinophil apoptosis (17). With a high affinity for,and high potency at, the glucocorticoid receptor, it is reasonableto predict that treatments with mometasone would lead to in-creased activation of the ubiquitous extrapulmonary glucocorti-coid receptors. However, the systemic bioavailability of inhaledmometasone furoate has been claimed to be 1% (18), signifi-cantly lower than that of any other ICS currently available, whichmay offset the increased potential for systemic activation.

This study was designed to compare the effects of mometa-sone furoate and fluticasone propionate on the hypothalamic-pituitary-adrenal axis at low, medium, and high therapeuticdoses. Previous work has looked at this issue by using peripheralblood levels of the steroid moieties as a marker of systemicactivation. However, as both fluticasone propionate and momet-asone furoate are highly lipophilic due to the position of anesterified lipophilic group at the 17-� position (19–21), they havelarge volumes of distribution, with a more extensive distributionof the drug in the fat soluble systemic tissues than in the water-soluble plasma (22). Thus, measurement of plasma corticosteroidconcentrations will underestimate the total systemic level ofcorticosteroid moiety. The detection of pharmacodynamic sys-temic bioactivity due to peripheral tissue glucocorticoid receptorstimulation will give a much better reflection of total systemicexposure. Hypothalamic-pituitary-adrenal axis suppression hasbeen shown to be one of the most sensitive markers of systemicbioavailability of glucocorticoids (23); indeed, measures of adre-nal suppression may be used as a surrogate marker for potentialadverse effects in other systemic tissues (24). The most sensitivemethod of detection of hypothalamic-pituitary-adrenal axis sup-pression is that of 24-hour measurements of plasma cortisollevels or urinary free cortisol excretion. Poor compliance issues,even within a controlled outpatient clinical trial environment,make a 24-hour urine collection impractical, whereas a 24-hourplasma profile requires patient confinement. The use of over-night and early morning urinary cortisol measurements has beenadvocated instead of a full 24-hour collection, as peak cortisolproduction occurs throughout the night, reaching a maximumin the early morning at approximately 8:00 a.m. (24). This hasbeen shown to be as sensitive as a full 24-hour urine or plasmacortisol collection, and markedly improves patient compliance (25,26). Fractionated endogenous cortisol secretion measured as anovernight, 10-hour urinary cortisol corrected for urinary creatininewas therefore selected as the primary outcome.

Fardon, Lee, Haggart, et al.: Mometasone and Adrenal Suppression 961

Figure 1. Flow chart demonstrating the study design. FP � fluticasonepropionate; MF � mometasone furoate; SM/ML � salmeterol andmontelukast.

METHODS

The study was conducted at the Asthma and Allergy Research Groupin Ninewells Hospital, Dundee as a single center trial. Patients wererecruited at random from the department database with the followingcriteria: all were nonsmoking adults age 18 to 65 years, had a clinicaldiagnosis of asthma for at least 6 months, had not received systemiccorticosteroids for 1 year, and did not exceed the licensed dose of ICS.All patients were deemed to be in good health based on medical history,physical examination, and routine laboratory blood tests. The localethics committee approved the study, and informed consent was ob-tained from all patients.

On entering the trial, all ICS and second-line asthma therapies werewithdrawn. Patients entered a 1-week period during which their asthmawas controlled by the administration of montelukast 10 mg once dailyand salmeterol 50 �g twice daily; during this time they received nocorticosteroid therapy allowing adequate washout of previously admin-istered ICS (9). Patients were allowed to use a salbutamol pressurizedmetered dose inhaler, as required throughout, as rescue therapy.

Patients were randomly assigned to two treatment groups. One group(n � 10) received fluticasone propionate via Accuhaler dry powder deviceat 250 �g twice daily for 2 weeks, followed by 500 �g twice daily for 2weeks, then 1,000 �g twice daily for a further 2 weeks. This was followedby a 1-week washout period during which patients received salmeterol,

TABLE 1. DEMOGRAPHIC DATA FOR PATIENTS COMPLETING THE STUDY PER PROTOCOL

ICS Dose (CFC-BDPSubject FEV1 % FEF25–75 FEF25–75 % 2nd Line Equivalent)Number Sex Age (yr) FEV1 (l) Predicted (L/min) Predicted ICS Therapy (�g/d)

1 F 61 1.61 79 1.82 65 HFA-BDP 8002 F 48 2.52 104 2.62 81 EFA-BDP 4003 M 65 1.81 63 1.1 35 BUD SM 8005 M 57 2.75 88 1.74 50 Naıve 06 M 67 2.67 88 1.88 59 HFA-BDP 2007 M 41 3.22 83 2.29 53 FP 1,0008 F 44 2.27 91 1.93 57 HFA-BDP 4009 F 60 1.93 91 2.41 85 Naıve 0

10 F 56 2.21 86 2.18 71 BDP 80011 F 51 2.77 88 2.02 59 FP SM 50012 F 52 2.15 89 2.8 89 Naıve 013 F 24 2.88 96 2.78 69 EFP-BDP 40014 M 38 3.73 101 2.97 69 FP 40015 F 43 3.01 104 3 85 Naıve 016 M 27 4.15 94 3.7 74 Naıve 017 M 56 3.36 91 2.45 65 Naıve ML 019 M 41 4.05 105 3.39 78 FP 1,00020 M 38 3.66 96 3.26 74 FP 1,00021 F 23 2.68 85 2.51 62 BUD 40022 F 56 2.27 96 1.81 60 FP 20023 F 53 2.38 104 1.89 62 BUD 20024 M 65 3.64 104 3.28 95 FP 1,000Mean 47.67 2.77 91.52 2.41 66.76 404SEM 2.77 0.15 2.13 0.14 3.00 80

Definition of abbreviations: EFP-BDP � extra-fine particle beclomethasone dipropionate; BUD � budesonide; CFC-BDP � chloroflu-orocarbon-propelled beclomethasone dipropionate; HFA-BDP � hydrofluoroalkane-propelled beclomethasone dipropionate; FP �

fluticasone propionate; ICS � inhaled corticosteroids; MF � mometasone furoate; ML � montelukast; SM � salmeterol; F �

female; M � male.

50 �g twice daily, and montelukast, 10 mg once daily. After this washoutperiod, patients were commenced on mometasone furoate via Twisthalerdry powder device at 200 �g twice daily for 2 weeks, then 400 �g twicedaily for 2 weeks, followed by 800 �g twice daily for the final 2 weeks.The other group (n � 11) received the same doses of fluticasone propio-nate and mometasone furoate, but reversed in order, as shown in Figure1. Patients visited the department between 8:00 and 9:00 a.m. after eachwashout period and after each 2-week treatment period. Montelukastand salmeterol were withheld for 36 hours, whereas mometasone furo-ate and fluticasone propionate were withheld for 12 hours before eachvisit. Pulmonary function was well maintained in all patients after with-drawal of all treatments. Ten hours before each visit, patients wereasked to void their bladder in the usual manner, and then collect allsubsequent urine overnight for analysis of 10-hour (10:00 p.m.–8:00 a.m.)overnight urinary cortisol and creatinine concentrations. Patients werealso asked to provide an early morning spot 8:00 a.m. urine sample foranalysis of urinary cortisol and creatinine concentration. This sampleconcluded their overnight collection and, as such, was included in theirovernight sample; however, the 8:00 a.m. sample was also analyzedseparately.

On arrival to the department, blood samples were taken for 8:00 a.m.plasma cortisol and serum osteocalcin after lying flat for 20 minutes. Spi-rometry was performed at each visit to assess FEV1, FVC, PEF, and meanforced expiratory flow during the middle half of the FVC (FEF25–75).Patients also recorded their PEF throughout the study, with the last 7days of run-in, washout, and each treatment being used for the purposeof analysis.

Cortisol and osteocalcin levels were determined by radioimmuno-assay (GammaCoat cortisol 125I RIA kit, DiaSorin, Stillwater, MN).The cortisol assay has a lower standard of 28 nmol/L with a sensitivityof 0.001 nmol/L; coefficients of variance for the assay were 4.4% withinmeasurements and 7.8% between measurements. The osteocalcin assayhas a lower standard of 0.25 nmol/L with a sensitivity of 0.001 nmol/L;coefficients of variance for the assay were 10% within measurementsand 10% between measurements. Creatinine measurements were madeusing a colorimetric assay method (Cobas-Bio, Roche Diagnostics,Lewes, UK) with a sensitivity of 1.2 mmol/L; coefficients of variance for

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TABLE 2. MEAN DIFFERENCES WITH 95% CONFIDENCE INTERVALS FOR DIFFERENCE BETWEEN BASELINE VISITS ACCORDINGTO SEQUENCE (I.E., FIRST OR SECOND IN ORDER IRRESPECTIVE OF SUBSEQUENT TREATMENT), AND ACCORDING TOTREATMENT (I.E., IRRESPECTIVE OF SEQUENCE ORDER)

Baselines According to Sequence Baselines According to Treatment

95% Confidence Interval for 95% Confidence Interval forthe Difference the DifferenceGeometric Geometric

Mean Fold Mean FoldDifference Lower Bound Upper Bound Significance Difference Lower Bound Upper Bound Significance

Corrected 10-h overnight urinary cortisol/creatinine 1.00 0.81 1.23 0.99 1.06 0.86 1.31 0.58

Uncorrected 10-h overnight urinary cortisol 1.02 0.80 1.32 0.84 1.15 0.90 1.46 0.268:00 A.M. urinary cortisol/creatinine 0.90 0.71 1.14 0.37 1.09 0.86 1.39 0.458:00 A.M. urinary cortisol 1.24 0.95 1.62 0.10 1.25 0.91 1.72 0.15Plasma cortisol 0.94 0.83 1.05 0.26 0.93 0.83 1.03 0.17Serum osteocalcin 0.97 0.84 1.11 0.62 0.91 0.80 1.03 0.12

the assay were 1.2% within measurements and 5.6% between measure-ments.

The primary outcome measure was overnight urinary cortisol/creati-nine ratio. A sample size of 18 patients completed per protocol was chosento power the study to detect 25% suppression (1.33-fold suppression)versus baseline in the primary outcome with a � error of 0.2. A p valueof � 0.05 was considered statistically significant. All other measureswere considered as being secondary. Urinary cortisol, plasma cortisol,and serum osteocalcin values were normalized by logarithmic transfor-mation. Data were then analyzed using covariate analysis of variancewith the Bonferroni correction for multiple pair-wise comparisons.Analysis was performed using SPSS for Windows release 11.0.0 (SPSSInc., Chicago, IL).

RESULTS

Twenty-one patients (12 females, 9 males), age 46.5 � 2.77 years(mean � SEM), completed the study per protocol. FEV1 was91 � 2.2% predicted, with FEF25–75 67 � 3% predicted. Onepatient dropped out due to intercurrent illness, one patient waslost to follow-up, and one patient left the study due to personalreasons. Data from these patients were not analyzed. Six patients

Figure 2. Individual patient data for corrected 10-hour urinary cortisol/creatinine ratio (nmol/mmol) shown by treatment, with geometricmean values shown for each treatment arm as a horizontal line. PBL �

pooled baseline. Doses given in �g/day. *Indicates a significant changefrom baseline (p � 0.05). For all treatments n � 21.

were steroid naıve at entry to the study, three were receivingsecond-line therapy, two patients were receiving salmeterol, andone patient was receiving montelukast. Of those patients takingICS, the dose was (mean � SEM) 566 � 77.7 �g chlorofluorocarbonpropelled BDP equivalent dosage. Demographic data are summa-rized in Table 1.

For all outcomes, there was no significant difference betweenthe first and second baseline visits in sequence after run-in andwashout, respectively, or between the baselines prior to eachrespective treatment arm, irrespective of sequence (Table 2).Thus, all data were analyzed comparing outcomes with a pooledbaseline.

When comparing treatments with pooled baseline, overnighturinary cortisol/creatinine was significantly depressed by boththe high and medium doses of fluticasone propionate and mo-metasone furoate. Values for geometric mean fold suppression(95% confidence interval for difference) from baseline are asfollows: fluticasone propionate 2,000 �g, 1.85 (1.21–2.82), p �0.002; fluticasone propionate 1,000 �g, 1.45 (1.07–1.96), p � 0.02;mometasone furoate 1,600 �g, 1.92 (1.26–2.93), p � 0.001; and

Figure 3. Individual patient data for uncorrected 10-hour urinary corti-sol levels shown by treatment, with geometric mean values shown foreach treatment arm as a horizontal line. Doses given as �g/day. *Indi-cates a significant change from baseline (p � 0.05). For all treatmentsn � 21.

Fardon, Lee, Haggart, et al.: Mometasone and Adrenal Suppression 963

TABLE 3. EFFECT OF FLUTICASONE PROPIONATE AND MOMETASONE FUROATE TREATMENT ONUNCORRECTED 10-HOUR URINARY CORTISOL CONCENTRATION

95% Confidence IntervalGeometric Mean Fold

Treatment Difference (From Baseline) Lower Bound Upper Bound Significance

FP 500 1.18 0.93 1.50 0.166FP 1,000 1.54 1.19 2.00 0.003*FP 2,000 1.98 1.43 2.73 � 0.001*MF 400 1.22 0.98 1.52 0.067MF 800 1.48 1.18 1.85 0.002*MF 1,600 2.09 1.46 2.98 � 0.001*

Definition of abbreviations: FP � fluticasone propionate; MF � mometasone furoate.Doses given as �g/day. For all treatments n � 21.* Indicates a significant change from baseline (p � 0.05).

mometasone furoate 800 �g, 1.39 (1.04–1.88), p � 0.02 (individ-ual patient data shown in Figure 2). Values for the low dosesof ICS were as follows: fluticasone propionate 500 �g, 1.06 (0.80–1.41), p � 1.00; and mometasone furoate 400 �g, 1.17 (0.88–1.55),p � 0.54. There was a similar pattern for uncorrected overnighturinary cortisol (Figure 3), with data shown in Table 3.

The high doses of both mometasone furoate and fluticasonepropionate significantly reduced 8:00 a.m. urinary cortisol/creati-nine, as shown in Table 4, and 8:00 a.m. plasma cortisol and serumosteocalcin, as shown in Table 5. Absolute values for all outcomesat completion of all treatment, baseline, run-in, and washout peri-ods, are shown in Table 6. There were no significant differencesin spirometry and diary card outcomes when comparing any treat-ment with baseline on postrun-in readings (Figure 4).

There were no significant differences between randomizedtreatments at any dose for any outcome variables.

DISCUSSION

The results of the present study have shown that for the primaryoutcome of overnight urinary cortisol/creatinine excretion, dose-related suppression was seen with both drugs. For secondaryoutcomes of 8:00 a.m. plasma cortisol, serum osteocalcin, and8:00 a.m. urinary cortisol/creatinine, there was significant sup-pression at only the highest doses.

We chose to assess the systemic bioavailability of mometa-sone furoate and fluticasone propionate using fractionated over-night urinary cortisol suppression as a surrogate marker of hypo-thalamic-pituitary-adrenal axis suppression. The effects ofinhaled corticosteroid on urinary cortisol have been shown tobe associated with concomitant suppression of the stimulatedcortisol response to a physiologic low dose of corticotrophinreleasing factor or corticotrophin (27, 28). The apparent discon-

TABLE 4. EFFECT OF FLUTICASONE PROPIONATE AND MOMETASONE FUROATE TREATMENTSON 8:00 A.M. URINARY CORTISOL/CREATININE MEASUREMENTS

95% Confidence IntervalGeometric Mean Fold

Treatment Difference (from Baseline) Lower Bound Upper Bound Significance

FP 500 0.95 0.70 1.27 1.00FP 1,000 1.23 0.90 1.67 0.31FP 2,000 1.85 1.15 2.99 0.01*MF 400 1.26 0.93 1.69 0.18MF 800 1.16 0.85 1.58 0.69MF 1,600 1.80 1.12 2.88 0.01*

For definition of abbreviations see Table 3.Doses given as �g/day. For all treatments n � 21.* Indicates a significant change from baseline (p � 0.05).

nect with both drugs at the medium dose between suppressionof overnight urinary cortisol/creatinine, but not 8:00 a.m. plasmacortisol, is similar to that previously reported by our group withother inhaled corticosteroid therapy (8).

Mometasone and fluticasone are similar in structure, bothbeing halogenated androstane derivatives with high topical tosystemic activity ratios (29). Their systemic effect will dependon not only the binding affinity of the ligand for the receptor,but also the systemic bioavailability (in turn affected by oral andpulmonary bioavailability), plasma protein binding, volume ofdistribution, elimination half-life, and terminal half-life of theglucocorticoid (30). Fluticasone propionate has an oral bioavail-ability of less than 1% (31), 90% plasma protein binding (32),a pulmonary bioavailability within the range of 16–30% de-pending on the inhalation device used (30), and a systemic bio-availability calculated to be 17% for the dry powder inhaler(33). The data obtained for the suppression of 10-hour overnighturinary cortisol by fluticasone propionate at 1,000 and 2,000 �gdaily are in keeping with previous studies (34, 35). Mometasonefuroate has been shown to have similar clearance, half-life, oralbioavailability, and first-pass metabolism as fluticasone propio-nate (18, 36, 37). This similarity is borne out in our study inwhich fluticasone propionate and mometasone furoate have sim-ilar effects on the primary and secondary outcome measures,with no statistical differences between clinically equivalent dosesof either moiety. However, as the protein binding of mometasonefuroate (99%) (38) is higher than that of fluticasone propionate(90%) (32), this would predict that the plasma levels of the freedrug would be 10 times lower with mometasone furoate (39),suggesting lower systemic effects. This is inconsistent with ourfindings of detectable systemic bioactivity with mometasone fur-oate 800 �g/day. One explanation suggested by other authors

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TABLE 5. EFFECT OF FLUTICASONE PROPIONATE AND MOMETASONE FUROATE ON THETREATMENT ON 8:00 A.M. PLASMA CORTISOL AND SERUM OSTEOCALCIN MEASUREMENTS

95% Confidence Interval8:00 A.M. Plasma Cortisol

Geometric Mean DifferenceTreatment (from Baseline) Lower Bound Upper Bound Significance

FP 500 1.057 0.880 1.268 1.00FP 1,000 1.108 0.961 1.277 0.24FP 2,000 1.505 1.079 2.098 0.02*MF 400 1.106 0.919 1.330 0.54MF 800 1.044 0.904 1.206 1.00MF 1,600 1.493 1.066 2.090 0.02*

95% Confidence Interval8:00 A.M. Serum Osteocalcin

Geometric Mean DifferenceTreatment (from Baseline) Lower Bound Upper Bound Significance

FP 500 11.393 7.594 18.536 1.00FP 1,000 12.812 9.134 18.926 0.50FP 2,000 31.984 12.007 125.367 0.02*MF 400 12.755 8.299 21.391 1.00MF 800 11.064 8.010 16.068 0.53MF 1,600 31.084 11.639 123.005 0.02*

For definition of abbreviations see Table 3.Doses given as �g/day. For all treatments n � 21.* Indicates a significant change from baseline (p � 0.05).

is that these adverse effects may be caused by active metabolitesof mometasone furoate with lower protein binding (39). In fact,mometasone furoate has a number of active metabolites, includingthe 6�-hydroxy metabolite and the free mometasone moiety(40). A true measure of the systemic bioavailability should in-clude measurements of mometasone furoate and all its activemetabolites. Thus, a measure of the hypothalamic-pituitary-ad-renal axis suppression, such as we have performed here, maygive a more accurate representation of the true overall systemicburden of mometasone furoate.

Safety data on the mometasone furoate dry powder inhalerwere published by Affrime and colleagues (41) showing thata daily dose of 1,600 �g of mometasone furoate significantlysuppressed the mean plasma cortisol levels at 7, 14, 21, and28 days. The present study confirms the suppression of plasmacortisol at a dose of 1,600 �g daily, but using the more sensitive

TABLE 6. ABSOLUTE VALUES FOR PRIMARY AND SECONDARY OUTCOMES AT COMPLETION OF ALL TREATMENT, RUN-IN,AND WASHOUT PERIODS, SHOWING GEOMETRIC MEANS AND SEM

Corrected 10-Hour Urinary Uncorrected 10-Hour 8:00 A.M. Urinary Cortisol/Cortisol/Creatinine (nmol/mmol) Urinary Cortisol (nmol/L/h) Creatinine (nmol/mmol) Plasma Cortisol (nmol/L) Serum Osteocalcin (nmol/L)

Geometric Mean SEM Geometric Mean SEM Geometric Mean SEM Geometric Mean SEM Geometric Mean SEM

FP Baseline 9.705 1.091 46.030 6.334 25.822 3.533 338.48 18.11 1.046 0.094FP 500 8.561 1.001 38.205 5.402 23.973 4.143 333.12 26.85 1.129 0.093FP 1,000 6.877* 0.727 29.230* 3.722 20.550 2.910 317.78 23.54 1.024 0.097FP 2,000 5.333* 0.854 22.761* 4.400 13.618* 2.701 233.88* 33.24 0.914* 0.098MF Baseline 9.389 0.980 40.928 3.839 22.903 2.920 364.79 24.60 1.183 0.095MF 400 8.314 1.050 36.432 4.097 20.022 4.191 318.34 22.28 1.080 0.105MF 800 7.119* 1.040 30.443* 3.970 21.682 3.031 337.18 20.88 1.026 0.082MF 1,600 5.319* 1.037 21.570* 4.994 14.027* 2.920 237.58* 26.66 0.917* 0.082Pooled Baseline 9.798 0.875 45.054 4.016 25.194 2.852 351.98 18.46 1.107 0.090

For definition of abbreviations see Table 3.Doses given as �g/day; n � 21 for all variables.* Indicates a difference from pooled baseline to a significance of p � 0.05.

assay of overnight urinary cortisol/creatinine, we have shownthat the suppression is also significant for 800 �g daily. The dataof Affrime and coworkers showed significant suppression of 24-hour AUC (area under the curve) plasma cortisol by 400 �gtwice daily of mometasone furoate at time points 7, 14, and 21days, but not at 28 days, when compared with placebo (42). Itis difficult not to suspect that the Day 28 result was spurious,and that the significant suppression of the 24-hour cortisol wouldcontinue at and beyond this time point.

Initial pharmacokinetic data suggested the bioavailability ofmometasone furoate was less than 1% for the dry powder inhaler(18). Careful analysis of this work has led to the suggestionthat the methodology employed in the study led to an invalidconclusion (39). A subsequent pharmacokinetic analysis hasshown a marked increase in plasma mometasone furoate levelsafter repeated dosing for 2 weeks compared with a single dose,

Fardon, Lee, Haggart, et al.: Mometasone and Adrenal Suppression 965

Figure 4. Diary card outcomes throughout the study. (A ) FEV1 (solidcircles) and FEF25–75 % (open circles) at each study visit. (B ) Average earlymorning PEF for 7 days before study visits. Doses given as �g/day. Forall treatments n � 21.

in keeping with a large volume of distribution, with equilibrationbetween blood and adipose tissues (43). In the same study, thesystemic bioavailability with 400 �g mometasone furoate twicedaily for a 2-week period was estimated at 11%, which is similarto the systemic bioavailability of fluticasone propionate, calcu-lated at 17% (33). This similarity in systemic bioavailability issupported by the findings of the present study.

As would be predicted, there was no improvement in pulmo-nary function comparing any dose of either inhaled steroid moi-ety with the baseline, as the washout period was covered witha maximal dose of long acting �2 agonist and montelukast, thus,maximizing pulmonary function parameters. There was no doseresponse shown for pulmonary function with either inhaled ste-roid, as the doses of ICS used were beyond the steep part ofthe dose response curve for pulmonary function.

It can be noted from Figure 3 that only eight patients showeduncorrected urinary cortisol concentrations of � 20 nmol/L/hourwhile taking 1,600 �g mometasone furoate daily, compared withsix patients taking 2,000 �g fluticasone propionate daily. How-ever, the numbers of patients with low values at moderate dosesof 800 �g of mometasone furoate and 1,000 �g of fluticasonedaily, were five and six, respectively, and at low doses of 400 �gmometasone furoate and 500 �g fluticasone propionate daily,two and three, respectively. Only one patient had abnormalvalues at baseline. This shows the potential risk of hypothalamic-pituitary-adrenal axis suppression with low doses of both flutica-sone propionate and mometasone furoate in susceptible patients.

In conclusion, our data refute the assertion that mometasonefuroate has negligible systemic bioavailability and a lower potentialfor systemic adverse effects compared with other inhaled corticoste-roids. Clinicians, therefore, need to be aware that mometasonefuroate has the potential for producing similar adrenal suppressionto that of fluticasone propionate at medium-to-high doses.

Conflict of Interest Statement : T.C.F. does not have a financial relationship witha commercial entity that has an interest in the subject of this article; D.K.C.L.does not have a financial relationship with a commercial entity that has an interestin the subject of this article; K.H. does not have a financial relationship with a

commercial entity that has an interest in the subject of this article; L.C.M. doesnot have a financial relationship with a commercial entity that has an interest inthe subject of this article; B.J.L. does not have a financial relationship with acommercial entity that has an interest in the subject of this article.

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