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Mometasone Furoate Dry Powder Inhaler: a Once-Daily Inhaled Corticosteroid for the Treatment of Persistent Asthma

Posted on: Thursday, 27 December 2007, 03:00 CST

By Karpel, Jill P Nelson, Harold

Key words: Asthma - Dry powder inhaler - Inhaled corticosteroids - Mometasone furoate - Prednisone ABSTRACT

Background: Mometasone furoate (MF), a potent synthetic inhaled corticosteroid (ICS) with a high affinity for the glucocorticoid receptor, is approved for use in the treatment of asthma.

Scope: Publications reviewed in this article were identified via searches of MEDLINE and EMBASE databases using the terms 'mometasone furoate AND pharmacology' and 'mometasone furoate AND asthma AND clinical trial'. Data from abstracts presented at respiratory society meetings, and relevant background information, are also reviewed.

Findings: In clinical studies, MF, administered by dry powder inhaler (MF-DPI), was effective in treating all severities of persistent asthma, improving pulmonary function, reducing asthma symptoms, and reducing or eliminating the need for oral corticosteroids. Once-daily dosing of MF-DPI was effective in patients with mild or moderate persistent asthma previously taking twice-daily regimens of inhaled corticosteroids (ICSs), and in patients taking only inhaled (beta^sub 2^-agonists for symptom relief. Once-daily dosing in the evening with MF-DPI 200 [mu]g conferred a greater benefit than morning dosing with MF-DPI 200 [mu]g. Patients with severe asthma who were dependent on oral corticosteroids (OCSs) and high doses of ICSs were able to achieve greater asthma control and reduce or even eliminate OCSs when switched to MF-DPI. In trials of up to 1 year in duration, MF-DPI was well tolerated, with the majority of adverse events considered mild or moderate in intensity. MF had low systemic bioavailability and no clinically significant hypothalamic-pituitary-adrenal-axis suppression at therapeutic doses. The DPI device is a multiple-dose inhaler with a counter containing agglomerates of MF and lactose. Patients of all severities of persistent asthma were able to generate and maintain airflow profiles necessary to provide a uniform and accurate dose.

Limitations: Only one study evaluated both morning and evening administration of once-daily doses, and one of the comparative clinical trials was an open-label study.

Conclusion: Once-daily administration of MF-DPI 200-400 [mu]g in patients with mild to moderate persistent asthma effectively improved lung function and asthma control. In patients with severe persistent asthma dependent on oral corticosteroids, treatment with MF-DPI 400 [mu]g BID permitted substantial reduction of oral corticosteroid use. All MF-DPI treatments were well tolerated and had minimal systemic effects.

Introduction

Role of inhaled corticosteroids in the treatment of asthma

Asthma is a chronic disease of the airways, with airway inflammation present in affected patients regardless of whether their signs and symptoms indicate the presence of mild, moderate, or severe disease1,2.

Inhaled corticosteroids (ICSs) have prominent anti-inflammatory effects and are the most effective controller medications. They have been shown to improve lung function, decrease airway hyperresponsiveness, reduce asthma symptoms, reduce the frequency and severity of exacerbations, and improve quality of life in patients with asthma. Treatment guidelines recommend daily treatment with an ICS for adults and children over 5 years of age with persistent asthma of any severity1,2.

Daily use of a low-dose ICS is recommended therapy for patients with mild persistent asthma. In patients aged >/= 12 years with moderate persistent asthma, the new guidelines state that the use of a medium-dose ICS or addition of a long-acting beta^sub 2^- adrenergic receptor agonist (LABA) to a low-dose ICS are considered equal options as the preferred therapies'. For severe persistent asthma, guidelines recommend combination therapy with medium- to high-dose ICS plus a LABA, and consideration of omalizumab and an oral corticosteroid (OCS) if needed (i.e., prednisone)1. To help assure that LABAs are used safely, the US Food and Drug Administration (FDA) issued a Public Health Advisory in November 2005 stating that LABAs should be used only as add-on therapy for patients whose asthma is not adequately controlled with medication such as low- to medium-dose ICS3. Asthma management guidelines recommend downward titration of ICS therapy to the lowest dose required to maintain control of asthma symptoms, a practice that helps to minimize systemic exposure to ICS treatments1,2.

Inhaled corticosteroids are generally well tolerated and safe at recommended dosages, with oral candidiasis and throat irritation or hoarseness as their most common adverse effects. However, their potential adverse effects related to systemic activity include hypothalamic-pituitary-adrenal (HPA)-axis suppression, delayed growth in children, decreased bone mineral density (BMD), cataracts, and skin thinning/easy bruising. All of these adverse systemic effects are or appear to be dose related, and evidence shows that the effects of ICSs on the bones, eyes, and skin are also related to the duration of therapy. In most cases when ICSs are used at recommended doses, the risk of adverse systemic effects do not outweigh the risks of uncontrolled asthma4.

Mechanism of action of inhaled corticosteroids

Eosinophils are the predominant inflammatory cells in asthma, and CD4^sup +^ T lymphocytes and mast cells also play important roles in asthmatic airway inflammation (Figure 1)5-7. Airway inflammation in asthma is mediated by a variety of cytokines secreted by T helper type 2 (Th^sub 2^) cells, including interleukin (IL-4, IL-5, IL-9, and IL-13), as well as the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and IL-1beta8. Important chemokines involved in the recruitment of inflammatory cells into asthmatic airways are RANTES (regulated on activation normal T cell expressed and secreted), eotaxin, and monocyte chemotactic protein-18-12. The pathways leading to eosinophilic airway inflammation are complex, involving many steps from hematopoiesis to eosinophil accumulation and activation5. It is important to note that eosinophilia is not distributed uniformly in the airways in asthma13 and that distal regions of the bronchial tree may be more prone to infiltration by eosinophils, as well as CD4^sup +^ lymphocytes, at night14,15. These nocturnal changes are consistent with the chronobiology of asthma, as evidenced by circadian variations in airway inflammation and worsening of lung function and symptoms at night in many patients16- 19.

ICSs act locally in the airways to block many of the inflammatory pathways activated in asthma. Some of their effects are achieved via direct actions on inflammatory cells such as eosinophils and alveolar macrophages, while others are achieved indirectly through actions on T lymphocytes that affect cytokine release5,20,21. The effects of ICSs include reduction of eosinophil recruitment, activation, and survival22-25; inhibition of cytokine release by Th^sub 2^ cells26-28 and airway epithelial cells29-32; inhibition of the synthesis of cell-adhesion molecules33-37; and indirect inhibition of leukotriene synthesis, through reduction in the numbers of eosinophils and mast cells and actions on alveolar macrophages and basophils38. Another prominent action of corticosteroids is the direct suppression of inducible nitric oxide synthase39, seen clinically as a reduction in exhaled nitric oxide when ICSs are used in asthma therapy40,41.

Corticosteroids act intracellularly, diffusing into target cells and binding to glucocorticoid receptors (GRs) in the cytoplasm. They achieve their effects partly by inhibiting transcription of genes that express mediators of inflammation, and also by neutralizing transcription factors. Messenger ribonucleic acid (mRNA) coding for inflammatory mediators can be found in T lymphocytes and eosinophils42, and also in bronchial epithelium and vascular endothelium43,44.

Figure 1. Asthmatic airway inflammation can occur as a response to exposure to common airborne allergens, such as housedust mites, animal dander, pollens, and fungi, or as a response to nonspecific asthma triggers, such as cigarette smoke, fog, cold air, exercise, and emotional stress. Airway-resident cells (mast cells and macrophages) begin to recruit other cells (initially T cells) that mediate inflammation. These and other cells involved in the process secrete cytokines and chemokines, or stimulate the expression of adhesion molecules. Eosinophils and mast cells are the two chief cell types that secrete tissue-destructive chemicals (e.g., leukotrienes) and histamine, which provokes bronchoconstriction. Hyperresponsiveness to allergens or to nonspecific asthma triggers is a major cause of asthma exacerbations

The predominant effect of corticosteroids is suppression of the synthesis of pro-inflammatory mediators, partly through the modification of genetic mechanisms that up- and down-regulate protein synthesis20. In the classic genomic pathway, the glucocorticoid (GC)-receptor complex migrates to the nucleus and binds to specific DNA sequences - called glucocorticoid response elements (GREs) - on target genes, increasing the expression of anti- inflammatory proteins21,45.

However, because the promoter regions of most inflammatory genes do not possess GREs, a nongenomic mechanism has been proposed to account for suppression of inflammatory molecules, such as cytokines and adhesion molecules46. In the nongenomic mechanism, the GC- receptor complex is believed to bind to transcription factors for proinflammatory genes, rather than the DNA itself46-48. Through protein-protein interactions, the GC-receptor complex effectively suppresses the actions of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappaB), two important transcription factors that increase the production of important inflammatory mediators. The GC- receptor complex also binds to and inhibits a transcription factor, termed the cyclic adenosine-5'-monophosphate (AMP) response element- binding protein (CREB)49. beta^sub 2^-adrenergic receptor agonists and NF-kappaB activate CREB, which binds to cyclic AMP response elements on genes50. AP-1, NF-kappaB, and CREB are unable to bind to promoter regions on genes when bound to the GC-receptor complex. These interactions between the GC-receptor complex and transcription factors suppressing the production of inflammatory mediators appear to occur in the cytoplasm, as well as in the nucleus. A number of synthetic corticosteroids have been developed for the treatment of inflammatory airway diseases (i.e., asthma and allergic rhinitis). This review focuses on a dry powder formulation of mometasone furoate (MF), which is administered using a breath-actuated dry powder inhaler (DPI) for the treatment of persistent asthma.

Methods

A MEDLINE/PubMed search using the terms 'mometasone furoate AND asthma' found 59 articles published from 1991 to 2006 that presented data from clinical efficacy and safety studies as well as in vitro and in vivo pharmacology studies of mometasone furoate. Clinical study articles selected for detailed review were those focusing on once-daily, evening (QD PM) dosing of MF-DPI. Additional information covered in this review includes publically disseminated data from abstracts presented at respiratory society meetings and relevant background information on airway inflammation, immunology, and the chronobiology of asthma.

Pharmacologic features of mometasone furoate

Pharmacodynamics

Low concentrations of MF bind avidly to GC receptors and are highly effective in blocking a wide range of inflammatory pathways activated in asthma. The anti-inflammatory potency of MF relative to other ICSs has been shown in cellular assays using important inflammatory markers (Table 1).

Table 1. Potency of MF and other ICSs in several molecular assays

In an in vitro comparative study51, MF was found to bind to the human GC receptor more avidly than fluticasone propionate (FP), budesonide (BUD), and triamcinolone acetonide (TAA). With regard to GC-receptor transactivation, MF was shown to be 5-fold more potent than FP and 10-fold more potent than BUD.

A study based on in vitro assays has compared the activity of MF at different receptor types to that of FP52. Although the two agents were indistinguishable with regard to their activity at GC receptors and neither had any activity at estrogen receptors, the activity of MF at progesterone receptors was higher than that of FP. It was concluded that systemic exposure of MF sufficient to cause HPA-axis suppression would be likely to activate progesterone receptors as well. This could, theoretically, interfere with the estrous cycle, but the potential clinical relevance of these in vitro findings is not known.

One in vitro study34 found that MF and FP were the most potent corticosteroids in inhibiting eosinophil survival sustained by IL- 5, and another in vitro study53 found that MF was at least 10 times more potent than beclomethasone dipropionate (BDP) at inhibiting the synthesis and release of the cytokines IL-1, IL-6, and TNF-alpha.

The accumulation of eosinophils and other leukocytes at sites of inflammation in the airways, an important feature of asthma, is regulated to a large degree by adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). Eosinophil adhesion at sites of bronchial inflammation appears to be mediated in part by ICAM-1, which is also an important cell-surface receptor for the majority of rhinoviruses54. Rhinoviruses are associated with many asthma exacerbations, and ICAM-1 plays an important role in inflammatory- cell recruitment following rhinoviral infection55. MF was shown to inhibit the rhinovirus-induced expression of ICAM-154, suggesting that a corticosteroid with high topical potency may hold promise in the management of virus-induced exacerbations of asthma. However, the clinical significance of this effect has not been proven.

VCAM-1 has also been shown to promote attachment of eosinophils to vascular endothelium, and MF more potently suppressed TNF-a- induced VCAM-1 expression than other currently available ICSs35.

After allergen challenge in mice, inhaled MF reduced the numbers of eosinophils in bronchoalveolar lavage fluid in a dose-dependent fashion56. In this in vivo study, MF also decreased mRNA levels of the inflammatory cytokines IL-4 and IL-5. In addition, MF-DPI has been found to reduce sputum eosinophilia57.

In summary, the anti-inflammatory actions and potency of MF have been extensively investigated in vitro as well as in animal studies. These studies indicate that MF is highly potent in binding to the GC receptor, modulating gene transcription, inhibiting the release of inflammatory mediators, and inhibiting the infiltration of eosinophils and other leukocytes into the lung tissue. However, the clinical relevance of these in vitro and animal study data is not known.

Pharmacokinetics

Plasma mometasone furoate concentrations

Systemic exposure to MF was assessed in several clinical studies in healthy volunteers and patients with asthma. In a randomized, crossover, single-dose study conducted in 24 healthy adults to determine absolute bioavailability, plasma MF concentrations were determined after a 400-[mu]g MF-DPI or an equivalent intravenous (IV) dose58. Plasma concentrations of MF were below the lower limit of quantitation (LOQ; 50pg/mL) in 10 of the 24 patients following administration of 400[mu]g MF-DPI. Plasma concentrations in the other 14 patients were not greater than three times the LOQ. Pharmacokinetic analyses were performed on the IV-dose results only, and the mean terminal-phase half-life of MF was 4.5 h.

The potential of MF-DPI to produce systemic effects on the HPA axis was assessed in a 28-day, randomized, parallel-group, placebo- controlled study conducted in 60 adults with mild to moderate persistent asthma59. Plasma concentrations of MF were determined following QD dosing of MF-DPI (400-[mu]g, 800 [mu]g, and 1200 [mu]g QD and 200[mu]g BID). Plasma MF concentrations were below the LOQ at all sampling times for up to 28 days in the majority of patients (75% of patients) in the 200-pg BID and in 25% of patients in the 400-[mu]g QD treatment groups. At a dose of 800 [mu]g MF-DPI QD for up to 28 days, the mean peak plasma concentrations (C^sub max^) ranged from 80.9pg/mL to 111 pg/mL, about two times the LOQ. At the highest dose (1200 [mu]g), which exceeds the anticipated recommended dosage of MF, mean C^sub max^ ranged from 123pg/mL to 243pg/mL.

In an open-label study of 24 patients with mild to moderate persistent asthma, MF-DPI was administered as a single dose of 400 [mu]g on Day 1, followed by MFDPI 400 pg BID for 2 weeks60. At the end of 15 days, there were quantifiable plasma MF concentrations in 23 of 24 patients, with a mean C^sub max^ of 151 pg/mL. Plasma levels of MF following MF-DPI 400-[mu]g and 800-[mu]g doses administered BID for 28 days were determined in a randomized, evaluator-blind, parallel-dose group, placebo-controlled study in 64 patients59. On Day 28, mean plasma MF levels were approximately 100 pg/mL and 180pg/mL for MF-DPI 400 pg and 800 [mu]g BID, respectively. Overall, plasma MF concentrations, determined in these clinical studies, show that systemic exposure to MF is low at the recommended dosage.

Absorption, metabolism, and excretion of mometasone furoate

Absorption, metabolism, and excretion of a single 1000-[mu]g dose of tritiated MF administered by DPI were assessed in healthy adult males58. MF and/or its metabolites were eliminated primarily in the feces (74%), and to a lesser extent in the urine (8%). MF was rapidly and extensively metabolized after DPI administration, with no evidence of a single major metabolite in feces, urine, or blood. Liver microsomes metabolized MF in vitro, whereas lung microsomes did not, suggesting that the small portion of MF that reaches systemic circulation undergoes extensive hepatic metabolism.

Clinical efficacy and safety studies

The clinical efficacy of MF-DPI has been extensively studied in controlled trials involving patients with asthma of varying severities61-71. Overall, these studies in patients >/= 12 years of age were designed to assess efficacy and safety in four relevant patient populations:

* mild to moderate persistent asthma previously treated with short-acting beta^sub 2^-adrenergic receptor agonists (SABAs) only;

* mild to moderate persistent asthma previously treated with other ICSs;

* moderate to severe persistent asthma previously treated with high doses of an ICS;

* severe persistent asthma previously treated with oral prednisone.

Clinical studies of MF-DPI have evaluated several different dosage regimens. The initial dose-ranging study of MF-DPI61, as well as two studies with other ICSs as active controls62,63, evaluated only BID dosing regimens of MF-DPI. Studies on QD dosing (vs. BID dosing) initially evaluated morning (QD AM) dosing64-66, and one of these66 also evaluated QD PM dosing. More recent studies focused on evaluations of the efficacy of MF-DPI with QD PM dosing (Table 2)67- 9,71. All but one of the QD PM studies included a placebo control group. The exception was a study that used FP administered BID via metered dose inhaler (MDI) to serve as an active comparator71. It is important to point out that prescribing information for MF-DPI72 states that QD doses of this drug should only be administered in the evening. This recommendation is based on the generally greater results achieved with QD PM doses than with QD AM doses, and on the direct comparison of QD PM dosing with QD AM dosing in a pivotal trial66. The performance of QD PM dosing with MF-DPI is consistent with the concept of asthma chronotherapy19 and allows for effective asthma control with low-dose therapy.

Table 2. Clinical efficacy studies of MF-DPI administered QD PM

The primary efficacy endpoint in most studies of MF-DPI was the change from baseline in forced expiratory volume in one second (FEV,). secondary endpoints included changes in both AM and PM peak expiratory flow (PEF) rates, forced vital capacity (FVC), forced expiratory flow rates (FEF), asthma symptom scores, nocturnal awakenings requiring albuterol, use of albuterol rescue, response to therapy, and effects on health-related quality of life. In the study involving patients with severe asthma who could not be weaned from prednisone while using high doses of other ICSs, the primary efficacy endpoint was the reduction in prednisone use70. Safety parameters evaluated in the clinical studies included adverse events, notably oropharyngeal effects, vital signs, HPA-axis function, and ocular effects.

Steroid-naive patients

In steroid-naive patients, low-dose MF-DPI (200 pg QD PM) has been found to be superior to placebo as initial controller therapy in patients with mild persistent asthma. A study in steroid-naive patients67 found that MF-DPI 200 pg QD PM was effective, significantly improving pulmonary function compared with placebo. Treatment with MF-DPI 200 pg QD PM significantly (p < 0.01) increased FEV, compared with placebo, with increases at endpoint of 16.8% (0.43 L) and 6.0% (0.16L), respectively (Figure 2). Significant improvements in FEV^sub 1^ were observed at the end of Week 1 and at every time point thereafter. Significant increases in AM and PM PEF, FVC, and FEF^sub 25-75%^ were also observed with MF- DPI 200 [mu]g QD PM treatment relative to placebo (p

The efficacy of PM versus AM dosing of MF-DPI was investigated in a 9-month extension73 of a 12-week placebo-controlled trial64 in patients previously using only SABA. Patients who entered the 9- month doubleblind phase were randomized to one of four treatment groups: MF-DPI 200 [mu]g QD AM and PM, and MFDPI 400 [mu]g QD AM and PM. The exact timing of PM dosing was not specified. Patients who switched from AM to PM dosing experienced improvements in both FEV^sub 1^ and AM PEF, regardless of the dose.

Figure 2. Mean +- SEM change from baseline in FEV^sub 1^ with MF- DPI 200 [mu]g QD PM and placebo over 12 weeks of treatment and at endpoint. * p < 0.01 versus placebo. FEV^sub 1^ = forced expiratory volume in 1 second; MF-DPI = mometasone furoate dry powder inhaler; QD PM = once daily in the evening; SEM = standard error of the mean. (Reproduced with permission from Bensch GW, Prenner B, Berkowitz R, et al. Once-daily evening administration of mometasone furoate in asthma treatment initiation. Ann Allergy Asthma Immunol 2006;96:536)

Patients with persistent asthma previously maintained on ICS therapy

Three trials were conducted to evaluate the efficacy and safety of MF-DPI administered once daily in the evening for patients previously using twice-daily ICSs66,68,69. All three trials found improvements in lung function and reductions in symptom scores, nocturnal awakenings, and rescue albuterol use for MF-DPI QD PM treatments compared with placebo. The effectiveness of QD and BID dosing of MF-DPI was compared in patients with mild to moderate persistent asthma previously treated with ICS. FEV^sub 1^ improved significantly by the end of a 2-week, open-label, runin phase in which all patients received MF-DPI 200 pg BID in place of their previously prescribed ICS (Table 2)66. Patients then were randomized to continue MFDPI 200 pg BID, or to receive MF-DPI 200 pg QD AM, 200 pg QD PM, 400 pg QD AM, or placebo in a 12-week double-blind phase. The improvement in FEV^sub 1^ that occurred during the open-label run-in was maintained in the double-blind phase for the MF-DPI 400 pg QD AM, 200 pg QD PM, and 200 pg BID groups, but not for the MF- DPI 200 pg QD AM and placebo groups (Figure 3)66. At endpoint, the mean changes in FEV^sub 1^ for MF-DPI 200 pg QD PM, 200 pg QD AM, 400 pg QD AM, 200 pg BID, and placebo were 0.03 L, -0.22 L, -0.01 L, -0.03 L, and -0.30 L, respectively. These values represented mean changes from baseline (at randomization) of 1.5%, -8.4%, -1.4%, - 0.6%, and -9.8%, respectively. With regard to effects on AM PEF, all four active treatments showed similar changes (between -1.8% and +2.2%) that were significantly greater than values for placebo (- 8.1%) at endpoint. Significantly greater effects of MF-DPI treatments compared with placebo were also observed for other secondary efficacy variables. Specifically, morning wheezing and difficulty breathing were significantly improved (p < 0.01) in all MF-DPI groups compared with placebo, and evening wheezing and difficulty breathing scores showed a similar pattern. All MF-DPI groups except the group taking MF-DPI 200 pg QD PM had significantly improved morning cough, nocturnal awakenings, and albuterol use (p

Two randomized, placebo-controlled, double-blind clinical studies, each 12 weeks in duration, were conducted to further investigate the efficacy and safety of MF-DPI 400 [mu]g QD PM in patients with persistent asthma previously maintained on ICS therapy (Table 2)6869. Unlike earlier studies evaluating QD PM dosing, both of these studies specified that PM doses should be taken in the late afternoon or early evening, preferably before dinner time. Both studies included MF-DPI 200 pg BID as a comparator, and they included a protocol-specified ICS reduction period of 2-4 weeks to ensure that patients were dependent on ICS therapy. During this period, the previous ICS dose was reduced by 50% at the first visit. To qualify for randomization, patients had to demonstrate a decrease of 10% or more in FEV^sub 1^ from the screening value after ICS reduction. They also had to demonstrate at least one of the following symptoms: use of at least 15 inhalations of rescue medication over the past 4 days (but no more than 12/day), a total asthma symptom score of at least four on at least 1 day, a 25% or greater decrease in AM or PM PEF, or at least one nocturnal awakening requiring rescue albuterol use. Patients were discontinued from the study if their FEV, decreased to less than 50% normal predicted values during the ICS-reduction period. During the treatment period, patients were discontinued if their FEV^sub 1^ decreased by >/= 20% from baseline. During either period, patients were discontinued if they had a serious asthma exacerbation requiring emergency treatment, hospital admission, or treatment with additional asthma medication (other than a SABA).

Figure 3. Mean +- SEM change in FEV^sub 1^ during openlabel run- in with MF-DPI 200 [mu]g BID, and over 12 weeks and at endpoint following treatment with MF-DPI 200 [mu]g BID, 200[mu]g QD AM, 200[mu]g QD PM, 400[mu]g QD AM, or placebo in patients with moderate persistent asthma previously treated with ICS. *p < 0.01 versus placebo; [dagger] p

In the study by D'Urzo et al.68, the following MF-DPI treatments were compared with placebo: MF-DPI 400 [mu]g QD PM as one 400-[mu]g inhalation, MF-DPI 400 [mu]g QD PM as two 200-[mu]g inhalations, MF- DPI 200 [mu]g BID, and MF-DPI 200 [mu]g QD PM. The mean increases in FEV^sub 1^ from baseline at endpoint (Figure 4) ranged from 0.41 L to 0.51 L with MF-DPI treatment. The increases in FEV^sub 1^ were significantly greater with all MF-DPI treatments compared with placebo (0.16 L; p < 0.001), and no significant differences were seen between the MF-DPI treatments. This study also found that MF- DPI 400 [mu]g QD PM was effective when administered as one puff from a device delivering 400 [mu]g/inhalation, and as two puffs from a device delivering 200 [mu]g/inhalation.

Treatment with all MF-DPI dosage regimens resulted in significant improvements in AM symptom scores for coughing, wheezing, and difficulty breathing, and also reduced use of rescue albuterol and decreased nocturnal awakenings requiring albuterol (p < 0.05 vs. placebo). The greatest improvements were observed in AM coughing scores. The use of albuterol rescue decreased by 27-58% in the MF- DPI groups (p < 0.001 vs. placebo), while albuterol use increased by 53% in the placebo group. It was also observed that nocturnal awakenings requiring albuterol rescue were reduced by 65-88% in patients treated with MF-DPI QD PM68. No significant differences were seen between the 400 [mu]g QD PM and 200 [mu]g BID treatments for any variable, and treatment with MF-DPI 400 [mu]g/day had significantly greater effects than 200 [mu]g QD PM on difficulty breathing scores. The other 12-week, double-blind, placebocontrolled study evaluated the effect of MF-DPI on pulmonary function and asthma symptoms in 268 adolescent and adult patients with mild to moderate asthma, previously using ICS therapy69. Following ICS reduction, patients were randomized to treatment with MF-DPI 400 [mu]g QD PM as one 400 [mu]g inhalation, MF-DPI 200 [mu]g BID, or placebo. Mean increases in FEV^sub 1^ from baseline with MF-DPI 400 [mu]g QD PM and MF-DPI 200 [mu]g BID were 0.47 L and 0.51 L, respectively, and were significantly greater than increases with placebo (0.08 L; p < 0.001). There was no significant difference between the MFDPI groups. Significant improvements in secondary measures of pulmonary function were also observed in both MF-DPI groups compared with placebo (p < 0.001).

Figure 4. Mean change from baseline in FEV^sub 1^ with MF-DPI 200 [mu]g QD PM, MF-DPI 400 [mu]g QD PM as two 200 [mu]g inhalations, MF- DPI 400 [mu]g QD PM as one 400 [mu]g inhalation, MF-DPI 200 [mu]g BID, and placebo over 12 weeks of treatment and at endpoint. *p

Comparisons with other inhaled corticosteroids

Studies in patients with moderate persistent asthma have compared the efficacy of twice-daily MF-DPI with twice-daily BDP61,74, BUD62, and FP63, and one study compared QD AM regimens of MF-DPI and BUD75. The efficacy of MF-DPI 100 and 200 pg BID in terms of improvement in FEV, was found to be comparable to BDP 168pg BID and FP 250 [mu]g BID, respectively. However, a total daily dose of MF-DPI 400 [mu]g administered as a BID or QD AM regimen was superior to BUD 400 [mu]g BID and 400 [mu]g QD AM, respectively, for improvements in FEV^sub 1^. More recently, a QD PM regimen of MF-DPI has been compared with FP administered BID71. In this 8-week, open-label study71, MF-DPI administered as 400 [mu]g QD PM (one 400 [mu]g puff/day) was compared with FP-MDI 250 [mu]g BID (four 125 [mu]g puffs/day) in 167 patients previously using FP-MDI or -DPI (Table 2). Both treatments improved FEV^sub 1^, the primary variable, by the second week of administration. Increases with MF-DPI and FP-MDI were 5% and 7% at endpoint, respectively, with no significant difference between treatments. In physicians' assessments at the end of study treatment, 62% of patients in the MF-DPI group were rated as improved or much improved, compared with 47% in the FP-MDI group (p < 0.01). These results demonstrate that MF-DPI administered QD PM is at least as effective as FP BID.

Patients with severe asthma previously dependent on oral steroids

The oral steroid-sparing effect of MF-DPI was investigated in a 12-week, randomized, double-blind, placebo-controlled trial in patients (N = 132) with severe persistent asthma dependent on prednisone70. MF-DPI 400 [mu]g and 800 [mu]g BID were found to significantly reduce (p < 0.01) patients' daily oral prednisone dose compared with placebo. In fact, daily prednisone usage decreased by 46% in the MF-DPI 400 [mu]g BID group and by 24% in the MF-DPI 800 [mu]g BID group. This contrasts with the placebo group which demonstrated a 164% increase in prednisone requirements. The numbers of patients completely eliminating prednisone were 40% and 37% using MF-DPI 400 [mu]g and 800 [mu]g BID, respectively, while no patients in the placebo group were able to completely eliminate prednisone usage. Similar results were seen in a study of oral steroid sparing among patients (N = 123) treated with MF-MDI 400 pg or 800 pg BID compared with placebo76.

Adverse events

Dosages of 200 [mu]g to 1600 [mu]g per day of MF-DPI were well tolerated in adults and adolescents in 12-week studies61-70,74,75. In active comparator studies, MF-DPI at daily doses of 200-800 [mu]g administered as once- or twice-daily regimens was as well tolerated as BDP 168 [mu]g BID61,74, BUD 400 [mu]g QD AM and 400 [mu]g BID62,75, and FP 125 and 250 [mu]g BID63,71. The most commonly reported treatment-related adverse events (AEs) were oral candidiasis, pharyngitis, and dysphonia. These events were typically mild to moderate in intensity, and similar to AEs seen with other ICSs. The incidence of AEs, including oral candidiasis, was generally lower with QD dosing. In all studies, there were no clinically meaningful changes in laboratory tests, electrocardiograms, or vital signs.

The long-term tolerability of MF-DPI has been investigated in two separate studies. In the first study73, a 3-month efficacy trial was extended by 9 months in 166 patients. MF-DPI 200 [mu]g and 400 [mu]g administered both QD AM and QD PM were well tolerated, with no change in the nature or severity of AEs when examined over time. In the second study77, patients with moderate persistent asthma (N= 239) received MF-DPI 200 [mu]g BID, 400 [mu]g BID, or 800 [mu]g QD or BDP 168 [mu]g BID for 12 months. The incidence of adverse events for all MF-DPI groups was similar to the BDP control group, with the majority of AEs mild or moderate in severity.

Evaluations of systemic activity

The systemic safety of MF-DPI has been studied in clinical trials that evaluated treatment effects on HPA-axis activity, pediatric growth, and BMD. These evaluations provide important information about the long-term systemic safety of MF-DPI. Measurement of HPA- axis suppression is a sensitive assessment of the systemic activity of ICSs. HPA-axis suppression by MF-DPI administered QD and BID was assessed primarily using two measures: the integrated 24-h area under the plasma Cortisol concentration time curve (AUC^sub 0-24^) and cosyntropin stimulation testing. The plasma Cortisol AUG^sub 0- 24^ is a sensitive indicator of basal Cortisol secretion, while cosyntropin stimulation testing provides an indicator of adrenal reserve78.

The findings of three separate studies on the effects of inhaled MF on the HPA axis have been published in a single article59, as summarized below. In the first of two 28-day safety studies, 60 adult patients with mild to moderate asthma were randomized to treatment with MF-DPI 400, 800, or 1200[mu]g QD AM, MF-DPI 200 [mu]g BID, or placebo59. Plasma Cortisol AUC^sub 0-24^ data were obtained on Days 0, 7, 14, and 28, and cosyntropin stimulation testing was performed at the end of treatment. No dose-related or time-related changes in the plasma Cortisol concentrations were observed. In addition, no significant effects of treatment on 8 AM plasma Cortisol concentrations or urinary free-cortisol excretion were observed. Furthermore, all patients had a normal response to cosyntropin stimulation testing following 28 consecutive days of treatment.

In the second 28-day safety study, 64 adult patients with mild to moderate persistent asthma were randomized to treatment with MF-DPI 400 or 800 pg BID, oral prednisone lOmg QD, or placebo59. All plasma Cortisol AUC^sub 0-24^ measurements in the prednisone group were significantly lower than in the MF-DPI treatment groups or placebo group (p < 0.01). Mean serum Cortisol AUC^sub 0-24^ values were highest in the placebo group, followed by the MF-DPI 400 pg BID and 800 pg BID groups, respectively (Figure 5). At the end of the study, differences between MF-DPI 800 pg BID (eight times the recommended starting dose for steroid-naive patients) and placebo (-21% to - 40%) were statistically significant but substantially less than the difference observed between oral prednisone and placebo (-64% to 72%). Cosyntropin stimulation testing demonstrated similar results59.

In the third study59, individuals (N = 16 per group) with moderate persistent asthma were randomized to 28 days of treatment with MF administered via MDI at doses of 400 or 800 pg BID, or FP- MDI 880 pg BID, or placebo. On Day 28, the mean serum Cortisol AUC was not significantly different for MF-MDI 400 pg BID compared with placebo. MF-MDI 800 pg BID and FPMDI 880 pg BID significantly decreased serum Cortisol AUC^sub 0-24^ on Day 28 by 22% and 55%, respectively, compared with placebo. While these data were quite reproducible, methodological questions regarding the sensitivity of these assays and comparisons with other agents have been raised79, particularly the finding that MF has less effect on the HPA axis than FP. It has also been noted that MF and FP both have relatively high lipophilicity and large volumes of distribution, which may affect their systemic activity. A randomized crossover study compared the effects of low, medium, and high doses of MF-DPI (n = 11) and FP-DPI (n = 10) on HPA-axis function, with overnight urinary Cortisol/ creatinine ratio (UCCR) as the primary variable80. Patients took sequential, escalating doses of MF-DPI 200, 400, and 800 [mu]g BID; and FP-DPI 250, 500, and 1000[mu]g BID. Significant suppression of urinary Cortisol was observed with the medium and high doses of both MF-DPI and FP-DPI, and significant suppression of 8 AM levels of plasma Cortisol and serum osteocalcin was observed with the high doses of both drugs. The medium dose of MF-DPI in this study (400 [mu]g BID) is the highest recommended dose, and the effects of MF-DPI on plasma Cortisol and serum osteocalcin were seen only at a dose (800 [mu]g BID) that is twice the highest recommended dose. All of the study doses of FP-DPI were within the recommended range.

Clinical studies provide further support that therapeutic doses of MF-DPI have no clinically relevant effects on the HPA axis. A 12- week doseranging study compared MF-DPI at doses of lOOpg, 200 [mu]g, and 400 [mu]g BID with BDP 168 [mu]g BID and placebo61. No significant differences in mean plasma Cortisol concentrations were found among the treatment groups at the end of the study, either before or after cosyntropin stimulation. A randomized third-party blind study81 compared HPA-axis effects following 14 days of treatment with MF-DPI 400 [mu]g QD AM, BDP-hydrofluoroalkane (HFA)- MDI 200 [mu]g BID, or BDP-chlorofluorocarbon (CFC)-MDI 400 [mu]g BID. Serum Cortisol levels (AUC0 24) decreased significantly less from baseline with MF-DPI than with either formulation of BDPMDI (p

Figure 5. Effects of inhaled MF-DPI administered twice daily (400 [mu]g BID or 800 [mu]g BID) and oral prednisone on the HPA axis measured by mean serum Cortisol AUC^sup 0-24^ concentrations over 28 days. Data reported as mean +- SEM. * p < 0.01 versus placebo; [dagger] p < 0.05 versus placebo. AUC^sub 0-24^ = integrated 24-h area under the plasma Cortisol concentration versus time curve; BID = twice daily; HPA = hypothalamic-pituitaryadrenal; MF-DPI = mometasone furoate dry powder inhaler; QD = once daily. (Adapted with permission from Affrime MB, Kosoglou T, Thonoor CM, et al. Mometasone furoate has minimal effects on the hypothalamicpituitary- adrenal axis when delivered at high doses. Chest 2000; 118:1542. Permission conveyed through Copyright Clearance Center, Inc.)

Two randomized, double-blind, placebo-controlled studies assessed potential BMD effects of MF-DPI after up to 2 years of treatment in steroid-naive patients 18-50 years of age receiving 2-4 times the recommended daily dose for the population studied. The first study found that MF-DPI 400 [mu]g BID had no significant effect on lumbar spine BMD compared with placebo (-1.57% vs. -0.43%, respectively; p = 0.207)72. The other study found that MF-DPI 200 pg BID had a small but significant effect on lumbar spine BMD, but not total femoral or femoral neck BMD, at the end of treatment (Week 104) compared with placebo (-1.43% vs. 0.25%, respectively; p = 0.016)88.

These effects were inconsistent between bone sites, within the normal range for young adults, and had no established relationships to clinical outcomes. The study results were consistent with evidence for doserelated reduction of BMD with other ICSs89,90.

Delivery systems

Inhaled corticosteroids are available in a variety of formulations and delivery systems, including pressurized MDIs, DPIs, and nebulizers. MF is delivered via an innovative breath-actuated, multiple-dose DPI with a built-in dose counter that is easy for patients to use properly. The MF-DPI contains a reservoir and a dose plate that measures a precise amount of medication with each actuation of the inhaler. When the MF-DPI cap is removed, the dose plate simultaneously rotates and meters MF from the DPI reservoir into a single dose hole (Figure 6). The number of doses remaining is indicated on the dose counter. Inhalation through the device causes a pressure drop that lifts and propels MF out of the dose hole, through the inhalation channel and into the swirl chamber. Two dose formulations of MF and anhydrous lactose have been developed to date. The MF-DPI with a metered dose of 220 [mu]g delivers 200 [mu]g per inhalation, and the MF-DPI with a metered dose of 440 pg delivers 400 [mu]g per inhalation. Only the MF-DPI device delivering 200 [mu]g per inhalation is available in the United States.

The United States Pharmacopoeia (USP) and European Pharmacopoeia (EP) compendial standards specify that 90% of inhalers tested must deliver between 75% and 125% of the claimed dose (USP) or mean dose (EP). A US FDA draft guidance requires that 90% of inhalers tested must deliver active drug within 80-120% of the label claim and that delivery from all units is within 75-125% of that claimed91. The MF- DPI meets these more stringent FDA draft guidance specifications92.

Figure 6. Schematic of mechanics of the MF-DPI operation. Removal of the cap meters a single dose of MF dry powder from the drug reservoir into a cup in the dose plate (A) and then rotates the dose plate so the metered dose is brought into alignment with the inhalation channel (B). The patient's inhalation draws air through the inlet in the base of the DPI, and drug particles are entrained in the air flowing through the DPI and out the nozzle (C). DPI = dry powder inhaler; MF = mometasone furoate

Particle size distribution

Particle size affects the efficacy of the ICS. The optimal particle size for an inhaled medication is generally considered to be in the range of 1-5 [mu]m91. Micronized particles within this size range are typically not free flowing because of particle adhesion and electrostatic charge. The formulation of MF with lactose (1 part MF to 5.8 parts lactose) into stabilized agglomerates enables the MF-DPI to overcome these flow problems and thus deliver precise doses. Approximately 35% of the claimed delivered dose was generated by the MF-DPI in the particle size range required for optimal distribution throughout the airways and into the small bronchiolar airways93. To date, lung deposition studies with the MF-DPI have not been completed. Studies with other DPIs have found lung deposition to range from approximately 5% to 40% of the metered dose. With the exception of devices at the lower end of this range, lung deposition is generally greater with DPIs than that with MDIs using CFC propellants, but lower than that with MDIs using HFA propellants94.

Patient airflow profiles

Patients with varying degrees of asthma severity have a range of inspiratory flow rates and DPI dose delivery must be reproducible across this range. Inspiratory airflow profiles with the Twisthaler (Schering Corporation, Kenilworth, NJ, USA) device were measured 12 weeks apart in 18 adult patients with mild to moderate asthma. At both measurement times, patients' inspiratory flow rates (IFRs) and rise times were generally well within the calculated specifications to ensure delivery of the precise dose of MF (>/= 20 L/min and < 300 ms, respectively)95. Another inhaler evaluation in seven patients with severe asthma found that all patients were able to achieve IFRs sufficient for adequate dose delivery96. Thus, the MF-DPI may be therapeutically useful to patients with a wide range of inspiratory flow rates.

Limitations

The studies reviewed herein were well designed with regard to inclusion and exclusion criteria, and were adequately powered to detect the specified treatment differences. With regard to conclusions that can be drawn from the efficacy and safety studies, one study reviewed here compared dosages of 200 [mu]g QD AM and 200 [mu]g QD PM66. In addition, the study comparing MF-DPI 400 [mu]g QD PM with FP-MDI 250 pg BID was an open label study71.

Conclusions

Inflammation plays a central role in the pathogenesis of asthma, and asthma treatment guidelines recommend ICSs as therapy for all severities of persistent asthma owing to their potent anti- inflammatory effects and proven clinical efficacy. MF-DPI is a breath-actuated ICS that combines efficacy, safety, and convenience of use for the management of patients with all severities of persistent asthma.

MF has a high affinity for the GR, correlating with its potency as a modulator of expression of key inflammatory mediators. These actions are consistent with effective anti-inflammatory effects at low doses. MF-DPI has been shown to be efficacious in treating all severities of persistent asthma, improving pulmonary function, and reducing asthma symptoms. QD dosing of MF-DPI was effective in patients with mild or moderate persistent asthma, and evening dosing was clearly better than morning dosing for MF-DPI 200 [mu]g and 400 [mu]g.

MF-DPI treatment is generally well tolerated. The incidence of treatment-related AEs with MF-DPI has been low, with the majority of AEs being mild to moderate in severity. MF appears to have low systemic bioavailability following inhalation from the MF-DPI at therapeutic doses. Dose-related HPA-axis suppression has been detected with MF-DPI, with significant effects at 800 [mu]g per day but none at 200 [mu]g per day in studies lasting up to 1 year. The effects of MF-DPI on BMD have been inconsistent, with significant reductions seen with MF-DPI 400 [mu]g/day in one study, but not with 800 [mu]g/day in another study. Also, MF-DPI at doses up to 100 [mu]g/day have shown no effect on 1-year growth, while a dose of 200 pg/day showed some effect that is consistent with a drug class effect.

The MF-DPI has a simple design that includes a dose counter, and it is easy to use. Delivery of MF via this novel DPI has been shown to be uniform across a range of clinically relevant inspiratory flow rates. In summary, studies have shown that MF-DPI is a potent ICS and that QD PM administration is effective for the majority of patients with persistent asthma. Its flexible dosing regimen provides effective asthma control and has a favorable safety profile. Moreover, it employs an easy-to-use inhaler that helps to keep asthma therapy simple for patients.

Acknowledgments

Declaration of interest: The authors are consultants to Schering- Plough, which supported the development of this manuscript. They thank Ken Kauffman, BSc, who provided editorial support.

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