Published ahead of print on June 7, 2004, doi:10.1164/rccm.200404-500OC
© 2004 American Thoracic Society doi: 10.1164/rccm.200404-500OC
Adrenal Suppression with Dry Powder Formulations of Fluticasone Propionate and Mometasone FuroateAsthma and Allergy Research Group, Department of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom 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 of Medicine and Therapeutics, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland DD1 9SY, UK. E-mail: b.j.lipworth{at}dundee.ac.uk
Mometasone furoate (MF) and fluticasone propionate (FP) are high potency inhaled corticosteroids. The systemic bioavailability of MF is claimed to be negligible, leading to a minimal potential for systemic adverse effects. We assessed the overnight urinary cortisol/creatinine as the primary outcome of adrenal suppression in 21 patients with persistent asthma (mean FEV1 = 91%). Patients were randomized in a crossover fashion to receive 2 weekly consecutive doubling incremental doses of either FP Accuhaler (500, 1,000, and 2,000 µg/day) or MF Twisthaler (400, 800, and 1,600 µg/day). For the 21 per protocol completed patients, there was significant suppression of overnight urinary cortisol/creatinine with high and medium doses of both drugs—as geometric mean fold suppression (95% confidence interval) from baseline: FP 2,000 µg, 1.85 (1.21–2.82, p = 0.002); FP 1,000 µg, 1.45 (1.07–1.96, p = 0.02); MF 1,600 µg, 1.92 (1.26–2.93, p = 0.001); and MF 800 µg, 1.39 (1.04–1.88, p = 0.02). For secondary outcomes of 8:00 A.M. plasma cortisol, serum osteocalcin, and early morning urinary cortisol/creatinine, there was significant suppression with MF and FP at the highest dose. Our data refute the assertion that MF has negligible systemic bioavailability and a lower potential for systemic adverse effects compared with FP.
Key Words: adrenal suppression • asthma corticosteroids • fluticasone • mometasone Inhaled corticosteroids (ICS) are the mainstay of treatment in persistent asthma (1–5). The exact mechanism of action leading to the beneficial effects of ICS in asthma is not fully understood; however, a key event is the binding of the glucocorticoid to the cytosolic glucocorticoid receptor (3, 5). The glucocorticoid receptor is present in a wide range of cells. Sustained elevation of plasma glucocorticoid levels stimulates these ubiquitous glucocorticoid receptors, leading to unwanted systemic side effects such as adrenal suppression, altered bone metabolism, and impairment of growth in children (5–9). Although the use of ICS in the long-term management of asthma is recommended, it is advised that the lowest effective dose of ICS should be prescribed to minimize these systemic side effects (1). There are concerns that even the currently advised levels of ICS can, in the long term, lead to systemic side effects. This has driven efforts to develop novel ICS moieties with improved therapeutic effect locally in the lung, with minimized systemic side effects. Mometasone furoate is a high-potency steroid currently licensed in the United Kingdom as a powder-lactose mixture administered by breath actuated dry powder inhaler. It has been shown to be highly effective in patients with mild-to-moderate persistent asthma (10–12). In vitro studies have shown mometasone furoate to have a binding affinity for the human glucocorticoid receptor that is approximately 22 times that of dexamethasone (13), 7 times that of triamcinolone acetonide, 5 times that of budesonide, and 1.5 times that of fluticasone propionate (14). Data show that mometasone furoate has a relative potency at the glucocorticoid receptor expressed as EC50 (the molar concentration of an agonist which produces 50% of the maximum possible response at the receptor) of 0.07 nmol/L with the respective values for fluticasone propionate and budesonide of 0.32 and 1.2 nmol/L (14). Furthermore, this rank order of potency has been confirmed in terms of inhibition of histamine release from primed respiratory epithelial basophils in vitro (15), in terms of interleukin-5 release from TH-1 cells (16), and in terms of induction of eosinophil apoptosis (17). With a high affinity for, and high potency at, the glucocorticoid receptor, it is reasonable to predict that treatments with mometasone would lead to increased activation of the ubiquitous extrapulmonary glucocorticoid receptors. However, the systemic bioavailability of inhaled mometasone furoate has been claimed to be 1% (18), significantly lower than that of any other ICS currently available, which may offset the increased potential for systemic activation.
This study was designed to compare the effects of mometasone furoate and fluticasone propionate on the hypothalamic-pituitary-adrenal axis at low, medium, and high therapeutic doses. Previous work has looked at this issue by using peripheral blood levels of the steroid moieties as a marker of systemic activation. However, as both fluticasone propionate and mometasone furoate are highly lipophilic due to the position of an esterified lipophilic group at the 17-
The study was conducted at the Asthma and Allergy Research Group in Ninewells Hospital, Dundee as a single center trial. Patients were recruited at random from the department database with the following criteria: all were nonsmoking adults age 18 to 65 years, had a clinical diagnosis of asthma for at least 6 months, had not received systemic corticosteroids 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 local ethics committee approved the study, and informed consent was obtained from all patients. On entering the trial, all ICS and second-line asthma therapies were withdrawn. Patients entered a 1-week period during which their asthma was controlled by the administration of montelukast 10 mg once daily and salmeterol 50 µg twice daily; during this time they received no corticosteroid therapy allowing adequate washout of previously administered ICS (9). Patients were allowed to use a salbutamol pressurized metered 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 device at 250 µg twice daily for 2 weeks, followed by 500 µg twice daily for 2 weeks, then 1,000 µg twice daily for a further 2 weeks. This was followed by a 1-week washout period during which patients received salmeterol, 50 µg twice daily, and montelukast, 10 mg once daily. After this washout period, patients were commenced on mometasone furoate via Twisthaler dry powder device at 200 µg twice daily for 2 weeks, then 400 µg twice daily for 2 weeks, followed by 800 µg twice daily for the final 2 weeks. The other group (n = 11) received the same doses of fluticasone propionate and mometasone furoate, but reversed in order, as shown in Figure 1. Patients visited the department between 8:00 and 9:00 A.M. after each washout period and after each 2-week treatment period. Montelukast and salmeterol were withheld for 36 hours, whereas mometasone furoate and fluticasone propionate were withheld for 12 hours before each visit. Pulmonary function was well maintained in all patients after withdrawal of all treatments. Ten hours before each visit, patients were asked to void their bladder in the usual manner, and then collect all subsequent urine overnight for analysis of 10-hour (10:00 P.M.–8:00 A.M.) overnight urinary cortisol and creatinine concentrations. Patients were also asked to provide an early morning spot 8:00 A.M. urine sample for analysis of urinary cortisol and creatinine concentration. This sample concluded their overnight collection and, as such, was included in their overnight sample; however, the 8:00 A.M. sample was also analyzed separately.
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. Spirometry was performed at each visit to assess FEV1, FVC, PEF, and mean forced expiratory flow during the middle half of the FVC (FEF25–75). Patients also recorded their PEF throughout the study, with the last 7 days of run-in, washout, and each treatment being used for the purpose of analysis. Cortisol and osteocalcin levels were determined by radioimmunoassay (GammaCoat cortisol 125I RIA kit, DiaSorin, Stillwater, MN). The cortisol assay has a lower standard of 28 nmol/L with a sensitivity of 0.001 nmol/L; coefficients of variance for the assay were 4.4% within measurements and 7.8% between measurements. The osteocalcin assay has 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 measurements and 10% between measurements. Creatinine measurements were made using a colorimetric assay method (Cobas-Bio, Roche Diagnostics, Lewes, UK) with a sensitivity of 1.2 mmol/L; coefficients of variance for the assay were 1.2% within measurements and 5.6% between measurements. The primary outcome measure was overnight urinary cortisol/creatinine ratio. A sample size of 18 patients completed per protocol was chosen to power the study to detect 25% suppression (1.33-fold suppression) versus baseline in the primary outcome with a ß error of 0.2. A p value of < 0.05 was considered statistically significant. All other measures were considered as being secondary. Urinary cortisol, plasma cortisol, and serum osteocalcin values were normalized by logarithmic transformation. Data were then analyzed using covariate analysis of variance with the Bonferroni correction for multiple pair-wise comparisons. Analysis was performed using SPSS for Windows release 11.0.0 (SPSS Inc., Chicago, IL).
Twenty-one patients (12 females, 9 males), age 46.5 ± 2.77 years (mean ± SEM), completed the study per protocol. FEV1 was 91 ± 2.2% predicted, with FEF25–75 67 ± 3% predicted. One patient dropped out due to intercurrent illness, one patient was lost to follow-up, and one patient left the study due to personal reasons. Data from these patients were not analyzed. Six patients were steroid naïve at entry to the study, three were receiving second-line therapy, two patients were receiving salmeterol, and one patient was receiving montelukast. Of those patients taking ICS, the dose was (mean ± SEM) 566 ± 77.7 µg chlorofluorocarbon propelled BDP equivalent dosage. Demographic data are summarized in Table 1.
For all outcomes, there was no significant difference between the first and second baseline visits in sequence after run-in and washout, respectively, or between the baselines prior to each respective treatment arm, irrespective of sequence (Table 2). Thus, all data were analyzed comparing outcomes with a pooled baseline.
When comparing treatments with pooled baseline, overnight urinary cortisol/creatinine was significantly depressed by both the high and medium doses of fluticasone propionate and mometasone furoate. Values for geometric mean fold suppression (95% confidence interval for difference) from baseline are as follows: fluticasone propionate 2,000 µg, 1.85 (1.21–2.82), p = 0.002; fluticasone propionate 1,000 µg, 1.45 (1.07–1.96), p = 0.02; mometasone furoate 1,600 µg, 1.92 (1.26–2.93), p = 0.001; and mometasone furoate 800 µg, 1.39 (1.04–1.88), p = 0.02 (individual patient data shown in Figure 2). Values for the low doses of ICS were as follows: fluticasone propionate 500 µg, 1.06 (0.80–1.41), p = 1.00; and mometasone furoate 400 µg, 1.17 (0.88–1.55), p = 0.54. There was a similar pattern for uncorrected overnight urinary cortisol (Figure 3), with data shown in Table 3.
The high doses of both mometasone furoate and fluticasone propionate significantly reduced 8:00 A.M. urinary cortisol/creatinine, as shown in Table 4, and 8:00 A.M. plasma cortisol and serum osteocalcin, as shown in Table 5. Absolute values for all outcomes at completion of all treatment, baseline, run-in, and washout periods, are shown in Table 6. There were no significant differences in spirometry and diary card outcomes when comparing any treatment with baseline on postrun-in readings (Figure 4).
There were no significant differences between randomized treatments at any dose for any outcome variables.
The results of the present study have shown that for the primary outcome of overnight urinary cortisol/creatinine excretion, dose-related suppression was seen with both drugs. For secondary outcomes of 8:00 A.M. plasma cortisol, serum osteocalcin, and 8:00 A.M. urinary cortisol/creatinine, there was significant suppression at only the highest doses. We chose to assess the systemic bioavailability of mometasone furoate and fluticasone propionate using fractionated overnight urinary cortisol suppression as a surrogate marker of hypothalamic-pituitary-adrenal axis suppression. The effects of inhaled corticosteroid on urinary cortisol have been shown to be associated with concomitant suppression of the stimulated cortisol response to a physiologic low dose of corticotrophin releasing factor or corticotrophin (27, 28). The apparent disconnect with both drugs at the medium dose between suppression of overnight urinary cortisol/creatinine, but not 8:00 A.M. plasma cortisol, is similar to that previously reported by our group with other inhaled corticosteroid therapy (8). Mometasone and fluticasone are similar in structure, both being halogenated androstane derivatives with high topical to systemic activity ratios (29). Their systemic effect will depend on not only the binding affinity of the ligand for the receptor, but also the systemic bioavailability (in turn affected by oral and pulmonary bioavailability), plasma protein binding, volume of distribution, elimination half-life, and terminal half-life of the glucocorticoid (30). Fluticasone propionate has an oral bioavailability of less than 1% (31), 90% plasma protein binding (32), a pulmonary bioavailability within the range of 16–30% depending on the inhalation device used (30), and a systemic bioavailability calculated to be 17% for the dry powder inhaler (33). The data obtained for the suppression of 10-hour overnight urinary cortisol by fluticasone propionate at 1,000 and 2,000 µg daily are in keeping with previous studies (34, 35). Mometasone furoate has been shown to have similar clearance, half-life, oral bioavailability, and first-pass metabolism as fluticasone propionate (18, 36, 37). This similarity is borne out in our study in which fluticasone propionate and mometasone furoate have similar effects on the primary and secondary outcome measures, with no statistical differences between clinically equivalent doses of either moiety. However, as the protein binding of mometasone furoate (99%) (38) is higher than that of fluticasone propionate (90%) (32), this would predict that the plasma levels of the free drug would be 10 times lower with mometasone furoate (39), suggesting lower systemic effects. This is inconsistent with our findings of detectable systemic bioactivity with mometasone furoate 800 µg/day. One explanation suggested by other authors is that these adverse effects may be caused by active metabolites of mometasone furoate with lower protein binding (39). In fact, mometasone furoate has a number of active metabolites, including the 6ß-hydroxy metabolite and the free mometasone moiety (40). A true measure of the systemic bioavailability should include measurements of mometasone furoate and all its active metabolites. Thus, a measure of the hypothalamic-pituitary-adrenal axis suppression, such as we have performed here, may give a more accurate representation of the true overall systemic burden of mometasone furoate. Safety data on the mometasone furoate dry powder inhaler were published by Affrime and colleagues (41) showing that a daily dose of 1,600 µg of mometasone furoate significantly suppressed the mean plasma cortisol levels at 7, 14, 21, and 28 days. The present study confirms the suppression of plasma cortisol at a dose of 1,600 µg daily, but using the more sensitive assay of overnight urinary cortisol/creatinine, we have shown that the suppression is also significant for 800 µg daily. The data of Affrime and coworkers showed significant suppression of 24-hour AUC (area under the curve) plasma cortisol by 400 µg twice daily of mometasone furoate at time points 7, 14, and 21 days, but not at 28 days, when compared with placebo (42). It is difficult not to suspect that the Day 28 result was spurious, and that the significant suppression of the 24-hour cortisol would continue at and beyond this time point. Initial pharmacokinetic data suggested the bioavailability of mometasone furoate was less than 1% for the dry powder inhaler (18). Careful analysis of this work has led to the suggestion that the methodology employed in the study led to an invalid conclusion (39). A subsequent pharmacokinetic analysis has shown a marked increase in plasma mometasone furoate levels after repeated dosing for 2 weeks compared with a single dose, in keeping with a large volume of distribution, with equilibration between blood and adipose tissues (43). In the same study, the systemic bioavailability with 400 µg mometasone furoate twice daily for a 2-week period was estimated at 11%, which is similar to the systemic bioavailability of fluticasone propionate, calculated at 17% (33). This similarity in systemic bioavailability is supported by the findings of the present study. As would be predicted, there was no improvement in pulmonary function comparing any dose of either inhaled steroid moiety with the baseline, as the washout period was covered with a maximal dose of long acting ß2 agonist and montelukast, thus, maximizing pulmonary function parameters. There was no dose response shown for pulmonary function with either inhaled steroid, as the doses of ICS used were beyond the steep part of the dose response curve for pulmonary function. It can be noted from Figure 3 that only eight patients showed uncorrected urinary cortisol concentrations of < 20 nmol/L/hour while taking 1,600 µg mometasone furoate daily, compared with six patients taking 2,000 µg fluticasone propionate daily. However, the numbers of patients with low values at moderate doses of 800 µg of mometasone furoate and 1,000 µg of fluticasone daily, were five and six, respectively, and at low doses of 400 µg mometasone furoate and 500 µg fluticasone propionate daily, two and three, respectively. Only one patient had abnormal values at baseline. This shows the potential risk of hypothalamic-pituitary-adrenal axis suppression with low doses of both fluticasone propionate and mometasone furoate in susceptible patients. In conclusion, our data refute the assertion that mometasone furoate has negligible systemic bioavailability and a lower potential for systemic adverse effects compared with other inhaled corticosteroids. Clinicians, therefore, need to be aware that mometasone furoate has the potential for producing similar adrenal suppression to that of fluticasone propionate at medium-to-high doses.
Supported by a University of Dundee Research Grant. This article has an online supplement, which is accessible from this issue's table of contents at www.atsjournals.org Conflict of Interest Statement: T.C.F. does not have a financial relationship with a 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 interest in 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. does not have a financial relationship with a commercial entity that has an interest in the subject of this article; B.J.L. does not have a financial relationship with a commercial entity that has an interest in the subject of this article. Received in original form April 14, 2004; accepted in final form June 7, 2004
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