Mometasone Furoate Has Minimal Effects on the Hypothalamic-Pituitary-Adrenal Axis When Delivered at High Doses

doi:10.1378/chest.118.6.1538

Chest

Volume 118, Issue 6, December 2000, Pages 1538-1546

https://doi.org/10.1378/chest.118.6.1538 Get rights and content

Study objectives:

To investigate the potential formometasone furoate (MF) to exert systemic effects followingadministration by dry powder inhaler (DPI) or metered-dose inhaler(MDI).

Design:

Three randomized, evaluator-blind, placebo-controlled, parallel-group, 28-day studies.

Patients:

Adults with mild-to-moderate persistentasthma.

Interventions:

Study 1 (12 patients pertreatment group; MF DPI at 200 μg bid, 400 μg qd, 800 μg qd, or1,200 μg qd). Study 2 (16 patients per treatment group; MF DPI at 400μg bid or 800 μg bid, or oral prednisone at 10 mg qd). Study 3 (16patients per treatment group; MF MDI at 400 μg bid or 800 μg bid, or fluticasone propionate [FP] at 880 μg bid by MDI).

Measurements and results:

Study 1. Plasma concentrationswere near the lower limit of quantitation (50 pg/mL) at the MF DPI400-μg qd dosage and approximately 250 pg/mL at the 1,200-μg qddosage. The area under the curve for serum cortisol concentrations over24 h (AUC₂₄) was essentially unaltered at alldoses. Study 2. Plasma levels over days 7 to 28 were 100.3 ± 5.9pg/mL (mean ± SEM) for MF DPI 400 μg bid, and 181.0 ± 10.9pg/mL for 800 μg bid. Although there were relatively low levels ofsuppression (19 to 25%) at earlier time points for MF DPI 400 μgbid, serum cortisol AUC₂₄ levels at day 28 were similar toplacebo. MF DPI 800 μg bid and oral prednisone both decreased serumcortisol AUC₂₄ levels at days 7 to 28 by 28.0 ± 8.3% and 67.2 ± 3.6%, respectively. The response to cosyntropin wasnormal in 15, 14, 11, and 1 of the patients in the placebo, MF DPI 400μg bid, MF DPI 800 μg bid, and prednisone groups, respectively. Study 3. MF MDI caused even less systemic exposure than by DPI. MF MDI800 μg bid (24.0 ± 3.1%) and FP (51.7 ± 3.8%) caused asignificant decrease in serum cortisol AUC₂₄ on days 14 to28. MF MDI 400 μg bid was similar to placebo treatment at all timepoints.

Conclusions:

The MF 800-μg bid dosage (1,600μg/d), which is twice the highest projected clinical dosage, represents the lower limit for consistently detectable systemic effectsof MF.

Section snippets

Materials and Methods

All three studies were conducted at the same research center(Arkansas Research Medical Testing Center) in patients with a historyof mild-to-moderate persistent asthma. The study protocols andstatements of informed consent were approved by the Arkansas Research Human Volunteers Research Committee prior to the start of the study. Subjects gave written informed consent prior to enrolling into thestudy.

Study 1

There were a total of 60 patients (12 in each treatment group)whose ages were 35.1 ± 1.2 years (mean ± SEM; range, 18 to49 years) and whose weights were 171.1 ± 3.0 lb (range, 127 to 220lb). There were 32 female and 28 male patients. The only patientreceiving inhaled corticosteroids (beclomethasone dipropionate, twopuffs as needed) prior to the study was in the placebo group.

In the treatment groups with the lower MF doses (200 μg/bid and 400μg/qd), plasma MF concentrations were below the LOQ at

Discussion

Twice-daily dosing with MF by DPI at a high total dose of 1,600μg/d (study 2) was the lower limit for establishing consistentevidence of low levels of systemic exposure within the time framestudied, as demonstrated by moderately reduced mean serum cortisol, AUC₂₄ values and failure to achieve a normalcosyntropin response in some patients. Additionally at this high dose, MF was detected in the plasma, although not in all patients. Theeffects of this dose of inhaled MF on HPA-axis function, as

References (18)

MD Brannan et al.
A systemic bioactivity comparison of double-strength and regular-strength beclomethasone dipropionate MDI formulations
Ann Allergy Asthma Immunol
(1998)
DI Bernstein et al.
Dose-ranging study of a new steroid for asthma: mometasone furoate dry powder inhaler
Respir Med
(1999)
AS Nayak et al.
Once-daily mometasone furoate dry powder inhaler in the treatment of patients with persistent asthma
Ann Allergy Asthma Immunol
(2000)
IC Crocker et al.
Glucocorticoids inhibit proliferation and interleukin-4 and interleukin-5 secretion by aeroallergen-specific T-helper type 2 cell lines
Ann Allergy Asthma Immunol
(1998)
SP Umland et al.
The inhibitory effects of topically active glucocorticoids on IL-4, IL- 5, and interferon-γ production by cultured primary CD4+ T cells
J Allergy Clin Immunol
(1997)
JH Toogood et al.
Bioequivalent doses of budesonide and prednisone in moderate and severe asthma
J Allergy Clin Immunol
(1989)
R Vargas et al.
Effect of fluticasone propionate aqueous nasal spray versus oral prednisone on the hypothalamic-pituitary-adrenal axis
J Allergy Clin Immunol
(1998)
KG Saag et al.
Low dose long-term corticosteroid therapy in rheumatoid arthritis: an analysis of serious adverse events
Am J Med
(1994)
PJ Barnes et al.
Efficacy and safety of inhaled corticosteroids: new developments
Am J Respir Crit Care Med
(1998)

There are more references available in the full text version of this article.

Cited by (89)

Comparative clinical pharmacology of mometasone furoate, fluticasone propionate and fluticasone furoate: Pharmacology of mometasone furoate, fluticasone propionate and fluticasone furoate
2022, Pulmonary Pharmacology and Therapeutics
To investigate the pharmacokinetics and effects on the hypothalamic-pituitary-adrenal (HPA) axis of mometasone furoate (MF), fluticasone propionate (FP) and fluticasone furoate (FF).
Study 1: Fourteen healthy participants received inhaled and intravenous MF (inhaled dose via Twisthaler) and FP (inhaled dose via Diskus), both given at 400 μg, using a randomised, single-dose, four-way crossover design. Study 2: Twenty-seven participants with mild to moderate asthma, who discontinued their corticosteroid medication for 5 days to obtain a baseline 24 h serum cortisol, received inhaled MF Twisthaler and FP Diskus, both given at 400 μg twice daily (BID), using a randomised, 14-day repeat dose, two-way crossover design. Study 3: Forty-four healthy participants were randomised to a double-blind, placebo-controlled, five-period crossover study where the following treatments were administered via the inhaled route for 7 days: FP Diskus (250, 500, 1000 μg BID), FF Diskus (100, 200, 400, 800, 1600 μg once daily [QD]) or placebo Diskus. In each study, 24-h serial blood samples were collected and assayed to assess concentrations of MF, 6β-hydroxy mometasone, mometasone, FP, FF and cortisol. Pharmacokinetic and serum cortisol parameters were estimated as geometric means and 95% confidence intervals (CI).
Study 1: For intravenous MF and FP, respectively: absolute bioavailability was 11.4% (95% CI: 7.5, 17.6) and 7.8% (6.3, 9.6); plasma clearance was 47 L/h (41, 52) and 60 L/h (52, 69); half-life was 7.4 h (6.9, 8.0) and 7.2 h (6.5, 8.0); and volume of distribution was 499 L (439, 567) and 623 L (557, 698). Inhalation of single dose MF or FP did not significantly affect serum cortisol (<10% reduction from baseline), whereas intravenous administration of MF or FP each changed serum cortisol by approximately −50% from baseline. Study 2: For MF and FP, respectively: area under the curve up to the last measurable concentration on Day 1 was 421 pg h/mL (270, 659) and 248 pg h/mL (154, 400), and on Day 14 was 1092 pg h/mL (939, 1269) and 591 pg h/mL (501, 696); absolute bioavailability was 12.8% (11.2, 14.2) and 8.9% (7.7, 10.2). On Day 14, 24-h serum cortisol change from baseline was −35% (−44%, −26%) and −18% (−28%, −5%) for MF and FP, respectively; the reduction was significantly greater for MF than FP (ratio for geometric adjusted mean serum cortisol concentration: 1.28 [1.04, 1.56]). Low plasma concentrations of 6β-hydroxy mometasone were detected after intravenous dosing (Study 1) and after multiple inhaled dosing (Study 2); mometasone was not detected in any samples. Study 3: Inhaled FP and FF had similar systemic bioavailability estimates (12.0% [11.0, 13.2] and 15.0% [12.0, 17.3], respectively), but a differential effect on the HPA axis which was in agreement with the known 1.7-fold higher glucocorticoid receptor-binding affinity of FF versus FP. However, for FP 250 μg BID and FF 100, 200 and 400 μg QD, reduction in serum cortisol was not significantly different from placebo. For higher doses, FP 500 and 1000 μg BID, and FF 800 and 1600 μg QD, changes in serum cortisol concentration relative to placebo were −30%, −70%, −41% and −90%, respectively. Repeat inhaled dosing of FP 1000 μg/day (within the therapeutic dose range) resulted in comparable cortisol suppression to MF in the therapeutic range (30% reduction); whereas for FF this occurred at more than 3-fold above the therapeutic dose range (644 μg/day).
Single inhaled and intravenous doses of MF and FP (400 μg) resulted in similar bioavailability and reductions in serum cortisol. Repeat dosing of inhaled MF and FP in the therapeutic range (800 μg/day) resulted in greater systemic exposure for MF, and a 35% reduction in serum cortisol that was 2-fold greater than for FP. The higher glucocorticoid receptor-binding affinity and bioavailability, lower clearance and the presence of active metabolites may contribute to the greater systemic exposure and effect on cortisol for MF. Repeat dosing of inhaled FP and FF resulted in similar systemic bioavailability but differed in terms of the dose required for comparable cortisol suppression to MF in the therapeutic range. Unlike FP and FF, MF has active metabolites that may contribute to its systemic effects, while device/formulation performance differences also exist between MF-containing products.
Oral viscous mometasone is an effective treatment for eosinophilic esophagitis
2020, Journal of Allergy and Clinical Immunology: In Practice
Inhaled corticosteroids: Ocular safety and the hypothalamic-pituitary-adrenal axis
2016, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
The percentage of cortisol suppression was greater for fluticasone propionate than for beclomethasone dipropionate. Mometasone furoate also had a dose-dependent effect on cortisol suppression.22 In this study, 64 patients aged 19 to 50 years with mild-to-moderate persistent asthma at the Arkansas Research Medical Testing Center were treated twice daily with 400 μg of mometasone furoate, 800 μg of mometasone furoate, 880 μg of fluticasone propionate, or placebo for 28 days.
Inhaled corticosteroids (ICSs) effectively deliver corticosteroids to target sites in the lungs and reduce systemic effects compared with oral corticosteroids, but long-term systemic exposure from inhaled corticosteroids remains a concern.
To discuss ICS systemic effects on the eye and the hypothalamic-pituitary-adrenal (HPA) axis.
Relevant publications were used to augment discussion.
The most common adverse effects of exogenous corticosteroids on the eye are secondary open-angle glaucoma and posterior subcapsular cataracts. Study findings conflict about whether ICS use is associated with increased risk of glaucoma or elevated intraocular pressure, but studies might not have addressed the question in the right population. Increased risk of glaucoma may be limited to a few susceptible individuals, such as individuals with a family history of glaucoma. Large population-based studies reveal that high daily doses or high lifetime exposure of ICSs is associated with a higher risk of posterior subcapsular cataracts. More research is needed to determine the risk from low to moderate doses during long periods. For the HPA axis, there are several measures for detecting systemic effects. Short-term measures are more sensitive for detecting the systemic effects of ICSs but have less predictive value in identifying clinically important adverse effects. Several studies have found that ICSs have a dose-dependent effects on cortisol suppression that can be used to estimate equivalent dosages among ICSs.
Because of systemic effects on the HPA axis, high doses of ICS should be avoided where possible. Adult patients undergoing high-dose or long-term ICS therapy should be monitored for cataracts.
Pharmacokinetics of indacaterol and mometasone furoate delivered alone or in a free or fixed dose combination in healthy subjects
2016, Pulmonary Pharmacology and Therapeutics
Citation Excerpt :
While a slight increase in systemic exposure for indacaterol as well as mometasone furoate was noticed in this study, the statistical analysis revealed that all the comparisons between the fixed-dose combination QMF149 and monotherapy treatments fulfilled bioequivalence criteria except for the Cmax,ss of mometasone furoate in the comparison between QMF149 and mometasone furoate 320 μg. Previous data indicate that inhaled doses up to 600 μg/day indacaterol administered via the Breezhaler® device up to 1 year [16] and 1600 μg/day (administered as 800 μg twice daily) of mometasone furoate in the Twisthaler® device up to 28 days [17] were not associated with any clinical safety concerns, therefore the slight increase in exposure of the individual components is judged as not clinically meaningful. Both indacaterol and MF delivered via the Breezhaler® device exhibit dose proportional pharmacokinetics.
QMF149 is a fixed-dose combination of the long-acting β₂ agonist, indacaterol and the corticosteroid, mometasone furoate that is currently under development for treatment of patients with asthma and chronic obstructive pulmonary disease. We describe here a study designed to assess any pharmacokinetic (PK) and/or biopharmaceutical interaction between indacaterol and mometasone furoate when administered via the Breezhaler^® device, either alone or in a free or fixed combination (QMF149) in healthy adult subjects.
In this randomized, open-label, four-way crossover study, subjects were randomized to receive indacaterol acetate 150 μg, mometasone furoate 320 μg, alone and as free combination of the individual components, or QMF149 (indacaterol acetate 150 μg/mometasone furoate 320 μg) once daily for 14 days in each period, followed by a 7-day washout between periods. PK profiles were characterized on Day 14 up to 168 h post-dose.
Indacaterol AUC_0-24h,ss and C_max,ss after administration of QMF149 were 13% [ratio: 1.13; 90%CI: 1.09, 1.17] and 18% [ratio: 1.18; 90%CI: 1.12, 1.25] higher, respectively, than indacaterol monotherapy. Mometasone furoate AUC_0-24h,ss and C_max,ss after administration of QMF149 were 14% [ratio: 1.14; 90%CI: 1.09, 1.20] and 19% [ratio: 1.19; 90%CI: 1.13, 1.26], higher, respectively than mometasone furoate monotherapy. The majority (three of four comparisons between QMF149 and monotherapy) of the 90% confidence intervals of the between-treatment ratios for AUC_0-24h,ss and C_max,ss were within the 0.80 to 1.25 interval and therefore fulfilled bioequivalence criteria. The 90% confidence interval for C_max,ss for MF for the QMF149 vs. monotherapy comparison was [1.13, 1.26]. Although no definitive data can be provided on the basis of the present study results, it is unlikely that the small observed differences in expsoure are clinically meaningful. Multiple inhaled doses of indacaterol and mometasone furoate, when administered alone, in free combination or as QMF149 were well tolerated.
The QMF149 fixed dose combination treatment showed comparable systemic exposure to the free combination and monotherapy treatments in terms of AUC_0-24h,ss and C_max,ss for both indacaterol and mometasone furoate, indicating an absence of clinically relevant PK or biopharmaceutical interactions. These data support further development of QMF149 without dose adjustment.
Impact of study design on the evaluation of inhaled and intranasal corticosteroids' effect on hypothalamic-pituitary-adrenal axis function
2014, Journal of Pharmaceutical Sciences
Citation Excerpt :
For the 21 per protocol completed patients, there was significant suppression at high and medium doses of both drugs, with geometric mean fold suppressions (95% confidence interval) from baseline as follows: FP 2000 μg, 1.85 (1.21–2.82, p = 0.002); FP 1000 μg, 1.45 (1.07–1.96, p = 0.02); MF 1600 μg, 1.92 (1.26–2.93, p = 0.001); and MF 800 μg, 1.39 (1.04–1.88, p = 0.02). This was consistent with the findings by Affrime et al.23,24 that demonstrated significant suppression at 800 μg twice daily dose of MF. It is noted, however, that a placebo control was not included in this study.
In part I of this review, an overview of the designs of hypothalamic–pituitary–adrenal (HPA) axis studies in the setting of inhaled corticosteroids (ICS) or intranasal corticosteroids (INS) use was discussed. Part II provides detailed discussion on the HPA axis evaluation results for each common ICS and INS, and how these results are possibly affected by the factors of study design. Significant adrenal suppression at conventional ICS/INS doses appears to be rare in clinical settings. The magnitude of cortisol suppression varies widely among different study designs. Factors potentially impacting this variability include: the choice of dose, dosing duration, assay sensitivity, statistical methodology, study population, and compliance. All of these factors have the potential to affect the extent of HPA axis effects detected and should be considered when designing or interpreting the results of a HPA axis study. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2963–2979, 2014
Hypothalamic-pituitary-adrenal axis effects of mometasone furoate/formoterol fumarate vs fluticasone propionate/salmeterol administered through metered-dose inhaler
2013, Chest
The effects of mometasone furoate and fluticasone propionate on the hypothalamic-pituitary-adrenal axis were compared when administered from combination metered-dose inhaler (MDI) products.
In a randomized, open-label, placebo-controlled, parallel group study, 66 patients with mild to moderate asthma received one of the following four treatments bid through an MDI for 42 days: mometasone furoate/formoterol (MF/F) 200 μg/10 μg, MF/F 400 μg/10 μg, fluticasone propionate/salmeterol (FP/S) 460 μg/42 μg, or placebo. Plasma cortisol concentrations were measured over 24 h on days −1 (baseline) and 42. Geometric mean ratio (GMR) and 90% CI for mean change from baseline to day 42 in 24-h plasma cortisol area under the curve (AUC) were calculated for each treatment. If the 90% CI for the GMRs fell within 70% to 143%, treatments were deemed comparable.
Mean baseline cortisol AUCs were similar across groups. Mean cortisol effects (change from baseline) were similar for MF/F 400 μg/10 μg and FP/S 460 μg/42 μg (GMR, 119%; 90% CI, 101%-140%). Effects of MF/F 200 μg/10 μg on cortisol AUC were similar to placebo (GMR, 92%; 90% CI, 78%-110%), whereas MF/F 400 μg/10 μg and FP/S 460 μg/42 μg lowered cortisol AUC vs placebo (GMR, 78% [90% CI, 66%-92%] and 66% [90% CI 56%-78%], respectively). All treatments were generally well tolerated.
MF/F 400 μg/10 μg or FP/S 460 μg/42 μg bid through an MDI led to similar reductions from baseline in mean cortisol AUC (22% and 34% lower than placebo, respectively), whereas the effect of MF/F 200 μg/10 μg was similar to placebo.

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Clinical InvestigationsASTHMAMometasone Furoate Has Minimal Effects on the Hypothalamic-Pituitary-Adrenal Axis When Delivered at High Doses

Study objectives:

Design:

Patients:

Interventions:

Measurements and results:

Conclusions:

Section snippets

Materials and Methods

Study 1

Discussion

Ann Allergy Asthma Immunol

Respir Med

Ann Allergy Asthma Immunol

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Am J Med

Efficacy and safety of inhaled corticosteroids: new developments

Am J Respir Crit Care Med

Clinical Investigations
ASTHMA
Mometasone Furoate Has Minimal Effects on the Hypothalamic-Pituitary-Adrenal Axis When Delivered at High Doses