Montelukast in the treatment of asthma and beyond

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1 For reprint orders, please contact Montelukast in the treatment of asthma and beyond Expert Rev. Clin. Immunol. 5(6), (2009) Zuzana Diamant, Eva Mantzouranis and Leif Bjermer Author for correspondence Departments of Allergology and Pulmonology, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands Tel.: Fax: Asthma is a chronic inflammatory disease affecting over 300 million people worldwide. The common association with allergic rhinitis and the presence of proinflammatory cells and mediators in the circulation of patients qualify asthma as a systemic disease. This characteristic and the fact that the gold-standard therapy for persistent asthma, inhaled corticosteroids, cannot suppress all components of airway inflammation and fail to adequately penetrate into the small airways, warrant the quest for effective systemic anti-asthma therapies. This review describes the most important controlled studies of montelukast, a once-daily leukotriene receptor antagonist, in asthma and allergic rhinitis in both adults and children. Montelukast is a systemically active drug with a targeted, dual mechanism of action, acting both as a bronchodilator and anti-inflammatory. In patients of all ages, montelukast has shown a favorable safety profile and was well-tolerated. Both as monotherapy or in combination with inhaled corticosteroids, montelukast produced clinically relevant improvements in asthma-related parameters, including symptoms, lung function parameters, quality of life and the number of asthma exacerbations. Furthermore, bronchoprotective effects have been reported both against specific and nonspecific bronchoactive stimuli. Similarly, in patients with allergic rhinitis, montelukast produced substantial improvements in symptoms and quality of life. Long-term studies aimed to determine its effects on airway remodeling are still lacking. Keywords: adults allergic rhinitis asthma children leukotriene receptor antagonist montelukast small airways Asthma is a highly prevalent disease and a major cause of morbidity and mortality. The Global Burden of Asthma Report [1] states that one person in 20 suffers from asthma a total of 300 million people of all ages worldwide. This figure is expected to rise in the next few years, particularly in urbanized areas. Our understanding of the pathophysiology of asthma has evolved from its initial perception as a dis order of the neuromusculature within the central airways, to subsequent recognition of the fundamental role of chronic airway inflammation. This inflammation was originally believed to be confined to the central airways; however, at present it is widely accepted that apart from the central, large- and intermediate-sized airways, the peripheral airways (<2 mm diameter) are of at least equal importance in the pathophysiology of asthma [2]. Furthermore, there is an association with atopy, and although they are distinct disease entities, asthma is closely linked to allergic rhinitis (AR) [3]. In addition, there is ample evidence for the systemic nature of asthma [4], expressed by blood eosinophilia and other systemic associations, such as atopic dermatitis [3,5], cognitive disorders and asthenia [4,6]. Association with AR For many years, the association between asthma and AR was primarily attributed to a shared allergic background. However, more recent evidence suggests that AR increases the risk of developing asthma by threefold in both atopic and nonatopic subjects [7,8]. Indeed, approximately 50% of allergic rhinitics have seasonal airway hyperresponsiveness or full-blown asthma, while more than 80% of patients with allergic asthma suffer from concomitant AR [3,9]. In these asthmatics, concomitant AR may be the cause of poor disease control [10], and it is known that the risk for loss of asthma control increases with rhinitis severity [11]. Apart from these epidemiological links, there is ample evidence that AR and asthma have similar pathogenetic and immunological mechanisms. AR is characterized by chronic inflammation of the nasal mucosa that shares many features of the lower airway inflammation observed in /ECI Expert Reviews Ltd ISSN X 639

2 Diamant, Mantzouranis & Bjermer asthmatics, including accumulation of mast cells and eosinophils, T-lymphocyte activation and enhanced cytokine expression [12]. In addition, noninvasive airway sampling has shown evidence of lower airway inflammation, in terms of enhanced sputum eosinophils and exhaled nitric oxide, in patients with seasonal AR both in and out of pollen season [13,14]. Hence, modern guidelines advocate a combined strategy for diagnosis and treatment of allergic asthma with concomitant AR, often termed allergic airways disease or combined AR and asthma syndrome (CARAS) [3], i.e., AsthmaRhinitis. Small airways inflammation & other systemic aspects However, airway inflammation in asthma is not restricted to the upper airways, but involves the entire bronchial tree, including the peripheral small airways. Inflammation of the peripheral airways is present in asthma of all severities, even in very mild disease. Interestingly, the inflammation in the peripheral airways seems to be somewhat different from what is seen in the central airways, with increased numbers of mast cells in close vicinity to airway smooth muscle cells [15] and high-affinity cysteinyl leukotriene-1 receptors (CysLT 1 R) [2]. Furthermore, peripheral airway inflammation appears to be located within the peribronchiolar, parenchymal part of the lungs that are not readily accessible for inhaled therapies [16]. In addition, clinically important features of remodeling seem to occur mainly in the small airways [17], underscoring the necessity of targeting peripheral inflammation in order to achieve optimal disease control. Furthermore, the presence of proinflammatory cells and mediators in the circulation qualifies asthma as a systemic disease and, therefore, warrants the use of systemic treatment modalities. Indeed, the early oral therapies (b2 agonists, theophylline and corticosteroids) already had the advantage of treating both the upper and small airways in combination with systemic aspects of asthma, but were limited by serious side effects [4,18]. While in the 1970s asthma was primarily regarded as an inflammatory and bronchospastic disorder of the central airways, it was logical to aim for local anti-inflammatory and bronchodilator treatment by the inhaled route [4,18]. At present, antiinflammatory treatment with inhaled corticosteroids (ICS) is still the first-choice therapy, both aimed to control and to cure persistent asthma [201,202]. However, recent studies have demonstrated that the gold-standard therapy (ICS with or without long-acting b2-agonists) does not achieve optimal control in all asthmatics [19], partly because ICS cannot fully reach all parts of the airways (i.e., the upper and the small airways) [20] and partly due to corticosteroid-refractory mechanisms [4]. In this respect, it has been shown that neither high doses of inhaled nor oral corticosteroids can suppress the production of leukotrienes, important proinflammatory mediators of inflammatory conditions, such as asthma [21,22]. Hence, there is a need for therapeutic strategies that identify and target systemic components of asthma not sufficiently controlled by ICS alone. Cysteinyl leukotrienes In 1938, the cysteinyl leukotrienes (CysLTs: LTC 4, LTD 4 and LTE 4 ) were first described as slow-reacting substance of anaphylaxis (SRS-A) by Kellaway and Trethewie [23], while their molecular structures were not identified until some 40 years later [24]. CysLTs are eicosanoids derived from arachidonic acid through the 5-lipoxygenase pathway within inflammatory and structural cells, including mast cells, eosinophils, basophils and bronchial epithelial cells. These potent bronchoconstrictor and proinflammatory mediators exert their biological effects through interaction with their receptors, CysLT 1 R and CysLT 2 R [25,26]. CysLT 1 Rs have been cloned and characterized by two research groups [27,28]. These receptors have been found on the surface of several structural cells (e.g., epithelial cells and smooth muscle cells) and inflammatory cells (including macrophages, monocytes and eosinophils). CysLT 1 Rs are known to mediate processes involved in the pathophysiology of asthma and AR, including submucosal edema, airway smooth muscle cell proliferation and contraction, mucus production, as well as recruitment and activation of inflammatory cells, mainly eosinophils (Figure 1) [29]. In mice, excessive expression of CysLT 1 R has been shown to be associated with profound airway eosinophilia, Th2 cytokine production and airway hyperresponsiveness [30]. This is in line with observations by Laitinen and colleagues, who found increased numbers of eosinophils in airway mucosal biopsies of asthmatic patients after LTE 4 inhalation [31] and Diamant et al., who demonstrated sputum eosinophilia following inhalations of LTD 4 in patients with similar asthma characteristics [32]. Recent evidence suggests that CysLTs may also play an important role in the process of airway remodeling through a CysLT 1 R-mediated increase of matrix proteins, including tenascin and laminin [33]. Furthermore, CysLT 2 R has also been found on a number of inflammatory cells, including monocytes and eosinophils as well as on structural cells, such as epithelial cells, endothelial cells, smooth muscle cells and fibroblasts. Although its role in the pathophysiology of asthma is much less specified, the CysLT 2 R may be implicated in the process of airway remodeling [34]. From the 1980s onwards, ample evidence has been provided that CysLTs and CysLT 1 R-mediated effects are both involved in key mechanisms of the pathophysiology in asthma [35,36] and in the allergic upper airway response in AR [3,37]. As a result, potent CysLT 1 R antagonists have been developed and marketed for the treatment of allergic airways disease. Presently, there are three specific leukotriene receptor antagonists (LTR As), all blocking the CysLT 1 R, licensed for clinical use: montelukast (Singulair [USA]; Singulair [Europe], Merck), zafirlukast (Accolate TM, AstraZeneca) and pranlukast (Ultair, Ono Pharmaceutical Co., Ltd). Global guidelines for the treatment of persistent asthma with or without AR The Global Initiative for Asthma guidelines (GINA) [202] recommend a stepwise approach to asthma treatment, with an ICS as the cornerstone of the treatment of mild and moderate persistent asthma in adults, with the addition of a long-acting b 2 -agonist (LABA) if insufficiently controlled. The guidelines address asthma as one organ disease and less attention is paid to the systemic aspects of the disease. The Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines were developed to address 640 Expert Rev. Clin. Immunol. 5(6), (2009)

3 Montelukast in the treatment of asthma & beyond Increased mucus secretion Decreased mucus transport Cationic proteins (epithelial cell damage) Increased release of tachykinins Sensory C fibers Eosinophil recruitment Blood vessel Cysteinyl leukotrienes Edema Smooth muscle Inflammatory cells (e.g., mast cells, eosinophils) Contraction and proliferation Figure 1. The multiple cellular effects of leukotrienes in the airways. Redrawn with permission from [29]. the management of AR, a common comorbidity of asthma [3]. Asthma in children is often associated with clinically important, systemic manifestations and as such represents a therapeutic challenge. Severe asthma in children has been shown to be strongly related to concomitant rhinosinusitis [38]. Moreover, allergic sensitization often involves several organs including the skin, GI tract, nose and lungs [39]. While in older children, exerciseinduced symptoms and bronchoconstriction are common and treatment compliance may be difficult to achieve with inhaled therapy [40], in infants, viral wheezing illnesses, particularly those caused by rhinoviruses are the most significant predictors of the subsequent development of asthma at the age of 6 years, in a birth cohort at high risk for atopy [41]. Indeed, several studies demonstrated that interaction between allergic sensitization in infancy and viral-induced bronchiolitis (mostly caused by rhinoviruses and respiratory syncytial virus) may result in the future development of asthma [42], with leukotriene-induced airway inflammation as part of the clinical phenotype [43]

4 Diamant, Mantzouranis & Bjermer With the apparent need to re-assess the role of systemic treatment modalities in the management of asthma and AR, AsthmaRhinitis as well as asthma and small airway inflammation, this paper provides an updated overview of recent clinical studies of the LTRA montelukast, a highly potent, once-daily CysLT 1 R antagonist. Pharmacology Montelukast sodium: chemistry & structure Montelukast sodium is an oral, potent and selective antagonist at CysLT 1 Rs, which mediates the bronchoconstrictor and proinflammatory actions of the CysLTs in asthma and AR. Montelukast sodium (MK-0476, L ) is marketed as Singulair by Merck & Co. in the USA and by Merck Sharp & Dohme elsewhere. The empirical formula is C 35 H 35 Cl.N.Na.O 3 S with a relative molecular mass of The structural formula is (R)-1-[[1-(3-(2-(7- chloro-2-quinolinyl)ethynyl)phenyl)-3-(2-(2-hydroxy-2-propyl) phenyl)propyl]thiomethyl] cyclopropaneacetic acid, sodium salt, shown in Figure 2. Available & recommended dosing Dose-finding studies indicate an optimum therapeutic dose of 10 mg/day in adults and adolescents [44,45]. Determination of the optimum daily dose of 5 mg in children aged 6 14 years [46] and 4 mg in infants as young as 6 months of age [47,203] is based on serum blood levels of the drug. For adults over 14 years of age, montelukast is provided as beige, rounded-square ( mm), film-coated tablets, engraved SINGULAIR on one side and MSD 117 on the other. Each film-coated tablet contains 10.4 mg of montelukast sodium, equivalent to 10 mg of montelukast-free acid. For children (6 14 years), montelukast sodium (Singulair Paediatric 5 mg) is provided as pink, round (9.5-mm diameter), biconvex cherry-flavored chewable tablets, engraved SINGULAIR on one side and MSD 276 on the other. Each chewable tablet contains 5.2 mg of montelukast sodium, equivalent to 5 mg of montelukast-free acid. For young children (2 5 years), montelukast (Singulair Paediatric 4 mg) is provided as pink, oval, biconvex, cherry-flavored chewable tablets engraved SINGULAIR on one side and MSD 711 on the other. For infants (6 24 months) and young children (2 5 years) 4 mg montelukast is also provided in a granule form, packed in an envelope and it is administered with food. The 4 mg tablet formulation, unlike the others, should be administered either 1 h before or 2 h after food, as it may be better absorbed in an empty stomach [48]. The dosage for all formulations is one tablet/dose daily at bedtime. The pediatric formulations for infants 6 months and older are presently registered in the USA and in all European countries. Pharmacokinetics In adults, montelukast (10 mg) has a mean oral bioavailability of 64%, and it is rapidly absorbed with a peak plasma concentration (C max ) being reached within 3 4 h (T max ) [203]. In children up to 8 years of age, administered 4 or 5 mg montelukast (chewable tablet), T max is approximately 2.6 h [49]. C max was shown to be 0.50 mg/l in children aged 6 8 years (5 mg), and 0.47 mg/l in those aged 2 5 years (4 mg) [49]. In infants 6 24 months old given a 4 mg dose of montelukast by oral granules, T max was approximately 2.2 h and C max was 514 ng/ml [47]. Overall, the pharmacokinetic profile of montelukast in patients aged as young as 6 months is comparable with that observed in adults [44]. The pharmacokinetics of montelukast are similar whether dosed in the morning or evening and are not significantly affected by food ingestion [203]. Following absorption, montelukast is more than 99% bound to plasma proteins, and is extensively metabolized by cytochrome P450 isoenzymes 3A4 and 2C9. Plasma clearance of montelukast is approximately 45 ml/min in healthy adults and is excreted along with its metabolites almost exclusively via the bile [203]. Drug interactions Cytochrome P450 3A4, 2A6 and 2C9 are involved in the oxidation of montelukast in human liver microsomes. Therapeutic concentrations of montelukast do not inhibit cytochrome P450 3A4, 2C9, 1A2, 2A6, 2C19 or 2D6, suggesting that self-induction of montelukast metabolism is unlikely to occur. Since montelukast sodium is metabolized by cytochrome P450 3A4 [50], caution should be taken when montelukast is coadministered with inducers of 3A4 such as phenytoin, phenobarbitone and rifampicin. Cl Figure 2. Montelukast. N S C H 3 OH CH 3 COOH Clinical pharmacology Kinetic binding studies have demonstrated the following rank order of potency for binding to the CysLT 1 R (LTD 4 site) for LTRAs: montelukast is equal to zafirlukast and both are more potent than pranlukast [51]. The specific and reversible antagonism of the CysLT 1 R by montelukast exerts two important effects, acting on airway smooth muscle cells and inflammatory processes. Unlike asthma drugs that act directly as bronchodilators, evidence from animal studies shows that montelukast is a very potent blocker of LTD 4 -mediated bronchoconstriction [52]. Initial proof-of-concept 642 Expert Rev. Clin. Immunol. 5(6), (2009)

5 Montelukast in the treatment of asthma & beyond studies of montelukast examined its ability to prevent LTD 4 -induced bronchoconstriction. In a placebo-controlled study in patients with mild persistent asthma, LTD 4 -induced bronchoconstriction was assessed by the provocation concentration required to reduce airway conductance (sgaw) by 50% (LTD 4 PC 50 ) [44]. After 4 h following single oral doses of 5, 20, 100 and 250 mg of montelukast, median LTD 4 PC 50 values were increased 85-, 113-, 161- and 181-fold, respectively, when compared with placebo. After 20 h following single oral doses of 40 or 200 mg montelukast, LTD 4 PC 50 values remained more than 50-fold higher than after placebo, indicating that montelukast produces sustained antagonism of LTD 4 -induced bronchoconstriction [44]. In susceptible individuals, montelukast has been shown to inhibit bronchoconstriction provoked by aspirin [53], inhaled allergen [54] and exercise (both in children and adults) [55]. Furthermore, maintenance therapy with 10 mg once-daily montelukast for 8 weeks provided greater and more sustained bronchoprotection against exercise-induced bronchoconstriction (EIB) than the LABA salmeterol (50 µg twice daily), both independent of or in addition to concurrent ICS treatment [56 58]. Both montelukast and salmeterol offered comparable protection against EIB at days 1 3, but a significant loss of bronchoprotection was noted at weeks 4 and 8 in the salmeterol group due to tachyphylaxis. In addition, montelukast has anti-inflammatory, mainly antieosinophil, properties [36,59]. Although some studies suggested that this effect may be limited to steroid-naive patients [60,61]; in asthmatics inadequately controlled by ICS, addition of montelukast led to a significant reduction in peripheral blood and induced sputum eosinophil counts [62], suggesting that leukotriene-driven inflammation is not fully suppressed by corticosteroid treatment. One potential explanation for this effect is the observation that in addition to inhibiting the growth of eosinophils locally, montelukast has similar effects centrally on bone marrow progenitor cells [63]. In children with asthma, montelukast has been shown to reduce levels of exhaled nitric oxide (eno), another marker of airway inflammation, both as monotherapy and on top of inhaled corticosteroids [64,65]. Apart from modulating the bronchoactive and proinflammatory effects of CysLTs, LTRA may also protect against several aspects of CysLT-induced airway hyperresponsiveness and airway remodeling [66,67], as CysLT 1 Rs have been found on the airway smooth muscle in both central and peripheral airways [25]. In line with these findings, in a study by Riccioni and colleagues, 12 weeks of treatment with montelukast (10 mg once daily) both as monotherapy and in combination with inhaled corticosteroids (budesonide 400 µg twice daily) decreased airway hyperresponsiveness in patients with mild-to-moderate persistent asthma [68]. Similarly, 4 weeks of treatment with montelukast significantly reduced regional air-trapping, and hence improved small airway function in patients with similar asthma characteristics [69]. In addition, two recent studies demonstrated improvements in markers of small airways function and inflammation in both children and adults with asthma after only short-term treatment (4 and 3 weeks, respectively) with montelukast, either as monotherapy or added to a fixed dose of ICS [70,71]. These observations represent the outcome of what might be termed double complementary effects, since first, LTRAs have been shown to possess antiinflammatory properties complementary to ICS [72,73] and second, being systematically active, LTRA may reach places, for example upper and small airways, that are not easily accessed by inhaled formulations [3,74]. Clinical efficacy Evaluation of clinical efficacy: disease-related markers For the assessment of efficacy of anti-asthma treatment, a combination of clinical and functional parameters can be used, sometimes in combination with inflammatory disease markers [2,75]. Functional end points that are widely used in clinical trials include forced expiratory volume in 1 s (FEV 1 ) and peak expiratory flow (PEF). However, these end points mostly focus on the larger airways and hence may not adequately address the pathophysiology within the small airways. Clinical correlates of asthma, notably exacerbations, nocturnal worsening and exercise-induced symptoms may more accurately reflect small airway function [76]. Consequently, current guidelines focus on improvement of disease control that is, preventing asthma exacerbations [3,202]. End points that are commonly used in the assessment of AR include nasal symptoms such as congestion, rhinorrhea, itching and sneezing, and eye symptoms [3]. In addition, validated (surrogate) markers of airway inflammation, such as eno and eosinophil counts in sputum or nasal samplings, are increasingly included in proof-of-efficacy trials and in clinical monitoring [77,78]. Studies in adults & adolescents (>14 years of age) Clinical efficacy of montelukast (10 mg once daily) in asthma was first demonstrated in three 12-week placebo-controlled studies involving 2471 patients with mild-to-moderate disease, in whom symptom scores and FEV 1 were assessed as primary end points [54,79,80]. In these studies, monotherapy with montelukast showed similar clinical efficacy to low-dose inhaled cortico steroids [81 83]. Although in the studies by Israel et al. and Malmstrom et al. beclomethasone (200 µg twice daily) had a greater effect on lung function (FEV 1 and PEF), montelukast showed similar improvements in all other outcome measures, including the percentage of asthma control days [82] and blood eosinophils [81], underscoring that lung function parameters may not fully reflect clinical efficacy. Interestingly, in all comparative studies in patients with mild-to-moderate persistent asthma, the numbers of responders and nonresponders appeared to be very similar in both treatment arms. In a comparative study, both montelukast and fluticasone propionate (FP) equally improved lung function, although unsurprisingly, FP more effectively reduced the steroid-sensitive inflammatory markers, eno and sputum eosinophils [84]. Interestingly, when looking at the response patterns of both treatment modalities, it appeared that, although the majority of patients responded equally well to both treatments, some responded better to FP while others had a better response to montelukast [85]. Asthma control days (ACD) were significantly increased both by FP (2.8 days/week) and montelukast (2.1 days/week). When comparing responses within individuals, 643

6 Diamant, Mantzouranis & Bjermer 29.3% of participants achieved at least one more ACD per week while on treatment with FP than during treatment with montelukast, whereas 12.2% achieved at least one more ACD per week during treatment with montelukast than during treatment with FP. In a 16-week study in 639 patients with mild-to-moderate persistent asthma, addition of montelukast to inhaled budesonide ( µg/day) significantly reduced the median percentage of asthma exacerbation days by on average 35%, as compared with placebo, independent of the ICS dose [86]. Additionally, montelukast also produced significant improvements in the secondary end points of the study (asthma-free days, nocturnal awakenings, b-agonist use and morning PEF). In a 12-week study of almost 900 patients receiving inhaled budesonide (800 µg/day), the effect of add-on montelukast therapy was compared with doubling the dose of ICS [87]. Overall, add-on montelukast was at least as effective as doubling the dose of budesonide, with improvement in PEF occurring more rapidly in the montelukast group, while in the double-dose ICS group significantly more respiratory adverse events (AEs), mainly upper airways infections, were seen [87]. In a sub analysis of this study involving 410 patients who were identified as having asthma with concomitant AR, the change in morning PEF from baseline was significantly higher (p < 0.03) in the group receiving add-on montelukast compared with doubling the dose of ICS (Figure 3), underscoring the need to treat both airway compartments to achieve optimal asthma control in patients with AsthmaRhinitis [88]. In patients not adequately responding to ICS, current guidelines recommend complementary therapy either with LABA or LTRA [202]. In a large, multicenter study of 1490 patients with mild-to-moderate persistent asthma, montelukast (10 mg once daily) was compared with salmeterol (50 µg twice daily) as addon treatment to fluticasone (100 µg twice daily) [62]. The primary outcome measure consisted of the number of severe asthma exacerbations, with symptom control, quality of life and lung function as secondary measures during 1 year of the respective treatments. After 52 weeks, montelukast was shown to be noninferior to salmeterol with regard to the proportion of patients experiencing an exacerbation (20.1 vs 19.1%, respectively; risk ratio: 1.05; 95% CI: ) [62]. Furthermore, both add-on treatments provided clinically relevant, significant improvements in nocturnal awakening and quality of life. While add-on montelukast significantly reduced eosinophil counts in induced sputum and in peripheral blood by virtue of its anti-inflammatory properties, add-on salmeterol significantly increased lung function parameters. Exercise-induced bronchoconstriction represents a specific challenge in asthma management. The bronchoconstrictive trigger is believed to be osmotic changes in the respiratory epithelium caused by hyperventilation and it has been shown to induce increased resistance within the peripheral airways [89]. Montelukast has been shown to effectively inhibit EIB in both adults and children with asthma [14]. Comparison between montelukast and salmeterol has convincingly shown that montelukast is superior to salmeterol for chronic treatment of asthmatics with EIB, as the effect by salmeterol was reduced due to the development of tolerance [56,57]. More recently, the effects of add-on treatment with montelukast and salmeterol were compared in fluticasone-treated asthmatics with EIB [58]. In these patients, the recovery from EIB and response to rescue medication was slower with add-on salmeterol as compared with add-on montelukast, while patients developed tolerance to salmeterol [58]. In another study, montelukast was compared with salmeterol evaluating exercise performance and gas exchange [90]. Montelukast was found to be superior to salmeterol with better bronchoprotective activity and improved oxygen pulse (i.e., oxygen uptake related to heart rate), indicating a better gas exchange with less ventilation perfusion mismatch [90]. In addition, concomitant treatment with ICS did not affect these outcomes [90]. Asthma with concomitant AR (AsthmaRhinitis) Apart from asthma, CysLTs have been found to play an important role in the pathophysiology of AR. Consequently, a series of controlled clinical trials in seasonal AR compared the efficacy of montelukast (10 mg once daily) with antihistamines and/or intranasal steroids or tested the efficacy of combination therapy with montelukast plus an antihistamine. Although montelukast has shown efficacy in AR alone, preferably when combined with an antihistamine [91 93], the clinical indication is to treat asthma with concomitant rhinitis, the so-called AsthmaRhinitis. In a large study in allergic rhinitics with concomitant asthma (n = 815), 2 weeks of treatment with montelukast (10 mg) significantly improved disease-related parameters as compared with placebo [94]. Interestingly, patients with more active and symptomatic disease in particular showed a superior response to treatment with montelukast. This is in line with previous data obtained from a subgroup analysis in the large Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy trial comparing add-on montelukast (10 mg) to budesonide (800 µg/daily) versus doubling the budesonide dose (1600 µg/ daily) [88]. Indeed, in the subgroup of asthmatic patients with concomitant rhinitis, combination therapy with montelukast provided significantly greater improvements both in the nasal parameters and in lung function measures as compared with doubling the dose of budesonide (Figure 3) [88]. These observations underscore the validity of the unified approach recommended by the ARIA guidelines [3] stated already by Grossman et al. 10 years earlier [95]. At present, there is still an apparent need to further study the pathophysiology of AsthmaRhinitis, as more severe upper airways inflammation has been shown to increase the risk of worsening of disease control with more severe exacerbations within the lower airways of asthmatics with concomitant AR [11]. Airway inflammation & remodeling Inflammation with structural changes in the lower airways (airway remodeling) represents a future challenge in asthma management. Fewer than 1% of adult asthmatics recover from their disease either spontaneously or after treatment [96]. ICS may affect some, but not all aspects of the remodeling process, even when introduced early in the course of the disease [97,98]. These aspects include long-term disease control and lung function decline (for a review, see [4]). One explanation for this relative lack of response 644 Expert Rev. Clin. Immunol. 5(6), (2009)

7 Montelukast in the treatment of asthma & beyond could be that ICS do not sufficiently control inflammation within the peripheral small airways [99]. Another, perhaps more important reason is that ICS treatment per se does not affect aspects of the peripheral inflammation. Antileukotriene therapy has a potential role in this process. LTD 4 and LTE 4 augment the expression of tenascin and laminin, important components of the reticulo epithelial basement membrane, and this process is completely inhibited by montelukast [33]. LTD 4 potentiate fibronectin-induced migration of human lung fibroblasts [100] and stimulate human smooth muscle cell proliferation [101]. Mast cells, the majority of which express LTC 4 - synthase, a key enzyme in CysLT production, are believed to play a key role in this remodeling inflammation [102]. Applying repeated allergen challenge in mice as a model for asthmatic airway remodeling, Henderson et al. demonstrated that this remodeling process could be substantially suppressed by montelukast [103]. Moreover, montelukast was able to reverse some of these changes even when introduced later in the course, after the remodeling process had been initiated [104]. In a biopsy study in patients with mild persistent asthma, 8 weeks of treatment with montelukast has been shown to inhibit the airway remodeling effects (increase in myofibroblasts) following low-dose allergen challenge [46]. Furthermore, there have been occasional case reports indicating that montelukast may have a beneficial effect reversing structural changes within the small airways [105]. However, despite good evidence from both human studies and animal experimental models of asthma, there are still insufficient data to support the clinical role of Change from baseline (l/min, LS mean ± SEM) Change from baseline (l/min, LS mean ± SEM) leukotriene modulator therapy in preventing airway remodeling and its consequences in clinical asthma. Convincing randomized long-term studies are still missing. Studies in children (aged 6 14 years) In children in particular, asthma management is often hampered by poor compliance to inhaled controller formulations. In view of its favorable safety profile and once-daily dosing regimen, montelukast seemed a promising candidate and hence in the past decade, many studies applying this drug in asthmatic children of different ages have been performed. In a study involving 336 asthmatic children (6 14 years, FEV % of predicted), Knorr and colleagues [106] demonstrated a significant increase in FEV 1 and a decrease in days with asthma Montelukast (n = 433) Budesonide (n = 425) Montelukast (n = 216) Budesonide (n = 184) Weeks Weeks p < 0.03 Figure 3. Subana lysis of the Clinical Outcomes with Montelukast as a Partner Agent to Corticosteroid Therapy (COMPACT) trial. (A) No difference could be seen between adding montelukast to budesonide 400 µg twice daily, compared with doubling the dose when all patients where included. (B) For those with concomittant rhinitis, montelukast proved to be superior. LS: Least square; SEM: Standard error of the mean. Redrawn with permission from [87]. exacerbations following 8 weeks of treatment with montelukast (5 mg). A subsequent analysis in 87 patients with milder disease (FEV 1 >75% predicted) confirmed that montelukast effectively improved FEV 1, nocturnal awakenings and quality of life [107]. In a crossover study including 279 children (mean age ± SD: 10.4 ± 2.2) with mild persistent asthma receiving ICS, addition of montelukast (5 mg) for 4 weeks significantly increased FEV 1, while significantly decreasing exacerbation days, b 2 -agonist usage and blood eosinophil counts [108]. In a 12-week, randomized, active-comparator study, treatment with montelukast (5 mg) was compared with that of inhaled budesonide (400 µg twice daily) in 63 children aged 8 14 years with mild persistent asthma and FEV 1 greater than 80% of the predicted value [109]. In addition to reductions in urinary LTE 4 levels, montelukast 645

8 Diamant, Mantzouranis & Bjermer produced clinically relevant improvements in airway function, daily symptom scores, nocturnal awakenings, b2-agonist usage and asthma exacerbations, similar to budesonide [109]. Although ample evidence has been provided for a role of CysLTs in the pathophysiology of EIB, until recently, no increases in CysLTs could be measured in patients with EIB following exercise [110]. In 2005, Carraro and colleagues found enhanced levels of CysLTs in exhaled breath condensate of asthmatic children with EIB following exercise as compared with asthmatic children without EIB or healthy controls (Figure 4), thus establishing the role of CysLTs in the pathophysiology of EIB [111]. In the past decade, several studies have evaluated the efficacy of montelukast on EIB in children with asthma. One study in asthmatic children (age range: 7 13 years) showed that one single dose of montelukast (5 mg) significantly reduced EIB with the maximal protective effect obtained at 12 h after dosing (p = 0.02) [112]. In children with atopic asthma, 1 week of treatment with montelukast (5 mg) produced significant reductions in both the immediate- and the late-phase airway response to exercise [113]. In a placebo-controlled, crossover study in 64 children, 8 weeks of treatment with montelukast significantly improved asthma symptom scores, the maximum percentage fall in FEV 1 after exercise, and the time to recovery [114]. These improvements were maintained even 8 weeks after discontinuation of treatment, suggesting a sustained effect of montelukast on airway hyperresponsiveness. Moreover, in another study in asthmatic children (6 12 years), 4 weeks of treatment with montelukast (5 mg) significantly protected against CysLT (pg/ml) p < 0.05 p < p = ns EIB Non-EIB Controls Figure 4. CysLT levels in exhaled breath condensate in asthmatic children, 7 18 years of age, with exercise-induced bronchoconstriction, without exerciseinduced bronchoconstriction and healthy control children. Open circles represent samples in which the CysLT concentration was less than the detection limit. Horizontal bars represent median values. CysLT: Cysteinyl leukotriene; EIB: Exercise-induced bronchoconstriction. Redrawn with permission from [111]. EIB without the development of tolerance to the bronchoprotective effect [115]. More recently, a 4-week randomized, placebocontrolled study in children (aged 6 18 years) with atopic asthma, compared the protective effect against EIB of monotherapy with montelukast (5 or 10 mg), with budesonide (200 µg; n = 20), budesonide (200 µg) plus montelukast (5 or 10 mg; n = 20), and budesonide (200 µg) plus salmeterol (9 µg; n = 20), respectively [116]. Although all active treatment regimens appeared effective against EIB, montelukast offered the greatest protection, both as a single and a combination therapy [116]. Several studies have examined the effect of montelukast as addon therapy in children with uncontrolled asthma despite treatment with inhaled steroids. In a 4-week study in 36 patients with asthma maintained on ICS, the addition of montelukast led to a significant increase in the number of rescue-free days (p < 0.002) compared with placebo [117]. Following a 20-week extension phase, the ICS dose in the montelukast group could safely be reduced by 17%, while in the placebo group an increase in ICS of 64% was observed. By contrast, in a 1 year active comparator study, in 6 14-year-old children with mild persistent asthma, montelukast (n = 495) was shown to be noninferior to inhaled fluticasone (100 µg twice daily; n = 499) in the primary end point of percentage asthma rescue-free days [118]. Alternatively, in a smaller study in children (5 15 years, mild persistent asthma) 12 weeks of treatment with montelukast (n = 30), when compared with inhaled budesonide (200 µg twice daily; n = 32), was similarly effective on symptom scores, lung function and rescue drugs [119]. Following treatment with montelukast (5 or 10 mg) for 8 weeks, children with mildto-moderate persistent asthma (n = 21; aged 9 18 years) had significantly lower residual volume, residual volume-total lung capacity ratio, airway resistance (Raw), better specific conductance (sgaw) and lower serum eosinophilic cationic protein (ECP) levels, as compared with placebo, suggesting an association between anti- inflammatory effects and decreased air trapping [120]. In another open study using forced impulse oscillometry (IOS) as a tool to estimate peripheral and central airway resistance, 46 children aged 6 14 years were treated with montelukast or placebo for 4 weeks. Montelukast produced a significant improvement in all IOS parameters, especially in the distal capacitive reactance Xrs5, believed to best reflect the peripheral airways [121]. In another crossover trial, Verini and colleagues evaluated the effects of 2 weeks of add-on therapy with montelukast versus salmeterol in 12 children with mild-tomoderate persistent asthma on low-dose inhaled fluticasone. Not unexpectedly, add-on salmeterol significantly increased 646 Expert Rev. Clin. Immunol. 5(6), (2009)

9 Montelukast in the treatment of asthma & beyond FEV 1 and decreased the residual volume, while add-on montelukast significantly decreased residual volume and eno [122]. The effect of montelukast (5 or 10 mg; n = 29) on central and peripheral airway function was compared with that of budesonide (200 µg; n = 29), budesonide (200 µg) plus montelukast (5 or 10 mg; n = 29), and budesonide (200 µg) plus salmeterol (9 µg; n = 29) in a randomized, placebo-controlled (n = 27), 4-week study in children 6 18 years old, with moderate atopic asthma. At the end of treatment, interrupted resistance R(int), specific airway resistance SR(aw) and FEV 1 improved significantly in all active treatment groups while forced expiratory flow (FEF) 25 75% improved significantly only in the budesonide plus montelukast group and the montelukast group [70]. Another 2-months crossover study in steroid-naive, atopic asthmatic children (aged 7 11 years; n = 48) compared the effect of budesonide (200 µg twice daily), budesonide 200 µg (twice daily) plus montelukast 5 mg daily, budesonide 200 µg plus formoterol 9 µg (twice daily) and budesonide (400 µg twice daily) on lung function and fractional exhaled nitric oxide (FENO). As compared with baseline, all treatments significantly increased FEV 1 and decreased FENO. However, the combination of montelukast and budesonide was superior in reducing FENO levels as compared with the other treatment regimen [123]. In another trial, school children with moderate-to-severe persistent asthma (n = 27) after a run-in period of 2.5 months with daily measurements of urinary LTE 4, cotinine, FENO and monitoring of albuterol use were randomized to add either montelukast or placebo to their regular controller medications, for another Change in daily albuterol usage per IQR increase in LTE 4 (%) Change in daily albuterol usage per IQR increase in LTE 4 (%) 2.5 months. At baseline, LTE levels were 4 positively associated with albuterol use. After 2.5 months, treatment with montelukast significantly reduced albuterol usage, especially in girls and in children with higher cotinine levels (Figure 5). In addition, children with high LTE 4 levels relative to FENO demonstrated significant declines in albuterol usage [124]. In an 18-week study, Szefler and colleagues evaluated markers associated with clinical response to ICS and LTRA in 126 children (aged 6 17 years) with mild-tomoderate persistent asthma in a double-blind, two-way crossover study, including 8 weeks treatment with either fluticasone (100 µg twice daily) or montelukast (5 10 mg once daily). Response to p = 0.01 BL Females Lower cotinine TRT p = 0.21 Males Higher cotinine both treatments was assessed by FEV 1 (defined as an increase of at least 7.5% from baseline) and relevant biomarkers (eno, PC 20 methacholine, serum IgE, ECP and total eosinophil counts) [125]. In terms of increases in baseline FEV 1, 17% of 126 children responded to both medications, 23% responded to fluticasone alone and 5% responded to montelukast alone, while 55% did not respond to either medication. Compared with children who did not respond to either medication, favorable response to fluticasone monotherapy appeared to be associated with overall higher BL p = 0.18 p = 0.01 BL Figure 5. Effect modifiers of the montelukast effect on LTE 4 -associated albuterol usage by children with asthma (n = 28; age 6 15 years). After a 2.5-month baseline period, children were randomized to receive daily montelukast or placebo for 2.5 months (treatment interval). Urine samples were collected twice a day, on 8 consecutive days, during the baseline and the treatment interval and LTE 4 and cotinine levels were measured. Use of albuterol was monitored daily. During the baseline interval, urine LTE 4 levels in all subjects were strongly associated with increased albuterol use (21.9% increase in albuterol usage per LTE 4 interquartile range increase [IQR; p = 0.003]) 2 days after urine collection. Shown are mean estimates and 95% CI for change in albuterol use per IQR in LTE 4, modified by (A) sex and (B) mean cotinine. Estimates are given for BL and TRT. BL: Baseline; IQR: Interquartile range; TRT: Treatment. Redrawn with permission from [124]. TRT BL TRT TRT 647

10 Diamant, Mantzouranis & Bjermer % days with worse asthma symptoms Boys Girls 2 5 years 6 9 years years % days with worse asthma symptoms p < 0.01 p < 0.12 p < NS NS p < years 6 9 years years Montelukast Placebo Age Age Figure 6. (A) Differences between montelukast and placebo treatment in percentages of days with worse asthma symptoms in boys according to age group. (B) Differences between montelukast and placebo treatment in percentages of days with worse asthma symptoms in girls according to age group. NS: Not significant. Redrawn with permission from [134]. baseline levels of eno, serum IgE, serum ECP, total eosinophil counts, and lower baseline FEV 1 and PC 20 to inhaled methacholine. By contrast, favorable response to monotherapy with montelukast was associated overall with younger age and shorter disease duration. Based on the results of their study, the authors concluded that asthmatic children with mild-to-moderate persistent asthma with low pulmonary function and/or high levels of markers of allergic inflammation should primarily receive ICS therapy, while children with another asthma phenotype could receive either ICS or LTRA [125]. Studies in children (aged ~5 years) The effect of montelukast (4 mg) has been studied in preschoolchildren (~5 years) with symptoms consistent with asthma or with recurrent viral respiratory infections, a known trigger of childhood asthma. In a large multicenter, placebo-controlled study in 689 children (aged 2 5 years) with persistent asthma, treatment with montelukast for 12 weeks produced significant improvements in day- and night-time asthma symptoms, asthmafree days, use of relievers and ICS, and physician global evaluation score [126]. In a placebo-controlled 1 year study in 549 children, aged 2 5 years, with viral-induced asthma, montelukast (n = 278) produced a significant reduction (mean: 31.9%) in asthma exacerbations, delaying the median time to first exacerbation by approximately 2 months along with the number of ICS courses [127]. The efficacy and safety of montelukast (4 and 8 mg) in treating recurrent respiratory symptoms in children was examined in a large, multicenter study of 3 24-month-old children, previously hospitalized for one or two episodes of respiratory syncytial virus (RSV) bronchiolitis with a positive test for RSV. Patients (n = 979) were randomized to placebo or to montelukast at 4 or 8 mg/day for 4 weeks (period I) and 20 weeks (period II). The primary end point was the percentage of symptom-free days (% SFD). No significant differences were seen between montelukast and placebo in % SFD over period I [128]. In contrast to the previous study of similar design but with a limited number of patients, montelukast did not show any beneficial effects in children with RSV bronchiolitis, possibly due to a different disease severity or phenotype in this multicenter cohort [128] compared with that of the previous study [129]. Interestingly, in an open-label study in 506 asthmatic children aged 2 5 years, long-term therapy with montelukast (4 mg once daily) mean duration 330 days, yielded similar rates of asthmarelated healthcare resource utilization [126], compared with those receiving standard care with cromolyn or ICS [129]. Another randomized study in 63 children (aged 2 6 years) with asthma-like symptoms compared the clinical efficacy of 3 months treatment with montelukast (n = 18) versus FP (n = 25) or placebo (n = 20).The primary outcome of the study comprised of daily symptom scores, while the secondary outcomes were rescue medication-free days, blood eosinophils and lung function. Although symptoms were improved in all treatment groups, only FP produced a statistically significant improvement compared with placebo, whereas only montelukast significantly reduced blood eosinophils [130]. In a 4-week, randomized, placebo-controlled study, the effect of montelukast (4 mg once daily) was evaluated in 24 children (aged months) with early childhood asthma (wheeze, allergy and a positive family history of asthma). As compared with placebo, patients treated with montelukast showed significant improvements in symptom scores, lung function (FEV 1 ) and FENO [131]. Similarly, in a placebo-controlled crossover study, montelukast (4 mg once daily) for 4 weeks has been shown to significantly reduce airway hyperresponsiveness in 26 preschool children (aged years) with mild, persistent asthma, as compared with placebo [132]. 648 Expert Rev. Clin. Immunol. 5(6), (2009)

11 Montelukast in the treatment of asthma & beyond Several studies have examined whether a short course of treatment with montelukast at the beginning of a viral upper respiratory tract infection (URTI) or an asthma episode would be able to modify the severity of the episode. In one recent study, children aged 2 14 years with intermittent asthma participated in a randomized, placebo-controlled trial over a 12-month period [133]. Montelukast (n = 107) or placebo (n = 113) was initiated by parents at the onset of each URTI or asthma symptoms and continued for 7 days or until symptoms had resolved for 48 h. There were 681 treated episodes (345 montelukast and 336 placebo) experienced by 202 patients. The montelukast group had 163 unscheduled healthcare visits for asthma, compared with 228 unscheduled visits in the placebo group (odds ratio: 0.65; 95% CI: ). There was a nonsignificant reduction in hospitalizations, specialist attendances, duration of episode, b-agonist and prednisolone use. However, montelukast significantly reduced symptoms (14%), night-time awakenings (8.6%), days off from school or childcare (37%) and parents time off work (33%) [133]. Another large study in 194 asthmatic children (aged 2 14 years) examined the impact of add-on montelukast versus placebo to their usual asthma therapy on viral asthma exacerbations between September 1 and October Children treated with montelukast compared with those with placebo experienced a 53% reduction in days with worse asthma symptoms and a 78% reduction in unscheduled visits for asthma (Figure 6). Montelukast was beneficial for all patients, irrespective of regular use of ICS and irrespective of colds during the trial [134]. Another study examined whether administration of montelukast, early in the course of a viral infection, might change the course of the disease. A total of 53 infants (mean age: 3.8 ± 3.5 months) with a first episode of acute bronchiolitis were randomly assigned to daily treatment of either 4 mg montelukast sachets or placebo, during all hospitalization days. The primary outcome was the length of stay, and secondary outcomes included the clinical severity score and changes in type 1 and 2 cytokine levels in nasal lavage. There were neither differences in length of stay nor in clinical severity score or in cytokine levels or types (Th2/Th1) between the two treatment groups [135]. It is possible that montelukast has no effect on healthy infants who experience their first episode of bronchiolitis when it is given after the disease has established. In this study, infants with previous episodes of bronchiolitis or ever treated with asthma medication prior to the episode of bronchiolitis were excluded from the study. In a recent randomized trial, 238 children aged months with moderate-to-severe intermittent wheezing were assigned to receive 7 days of either budesonide inhalation suspension (1 mg twice daily), montelukast (4 mg daily), or placebo in addition to albuterol with each identified respiratory tract illness (RTI). The primary outcome was the proportion of episode-free days (EFDs) during the 12 month trial. The three treatment groups did not differ in proportions of EFDs (p = 0.66), in oral corticosteroid use, healthcare use, quality of life or linear growth. However, during RTIs, budesonide and montelukast therapy led to modest reductions in trouble breathing (38 [p = 0.003] and 37% [p = 0.003], respectively) and interference with activity scores (32% [p = 0.01] and 40% [p = 0.001], respectively) that were most evident in patients with positive asthma predictive indices [136]. Recommendations for young children Based on the discrepancies in response to ICS or LTRAs in children with wheezing within this age group, in whom a diagnosis of asthma is difficult to make, a European Respiratory Society (ERS) task force was created in order to conclude on the phenotypes and the different treatment choices for recurrent wheezing in preschoolers. Two wheezing phenotypes were identified for this age group: The episodic (viral) and the multi-triggered wheezing. According to the ERS task force, montelukast was recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes and the fact that preschoolers can possibly move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit [137]. Postmarketing experience In a retrospective, cross-sectional survey of routinely collected clinical information from 56 centers in the UK, data were reviewed from 1351 eligible patients with asthma who had been treated with montelukast [138]. According to independent assessment, 66.4% of patients experienced an improvement in their asthma while on montelukast treatment. In these patients, montelukast produced clinically relevant decreases in asthma-related sleep disturbance (64.3%) and activity symptoms (63.9%). Interestingly, a relatively larger proportion of children presented with much or dramatically improved disease (41.3 vs 33.5% of adults). The largest proportion of responders was seen among those with mild-tomoderate disease. In addition, 40.4% of patients were recorded as having coexisting rhinitis; among 211 patients for whom a response was recorded, 54.5% showed an improvement in rhinitis [138]. Another observational post hoc study included 344 patients with asthma and rhinitis from Italy, Spain and Poland. Patients with mild persistent asthma and concomitant rhinitis treated with ICS/ LABA (n = 163) or ICS alone (n = 181) received montelukast (10 mg once daily) as add-on treatment for 1 year. The outcome variables included the need for additional medication for asthma and/or rhinitis and the occurrence of severe asthma exacerbations during the year after initiation of montelukast add-on therapy. Overall, as compared with the previous year, during the addmontelukast treatment significant reductions were observed in most of the studied variables, including use of oral corticosteroids (from 13.1 to 2.3%), severe asthma exacerbations (from 27 to 5.5%) and emergency room visits (from 16.6 to 2.6%). There was no significant difference between the two treatment groups, indicating that montelukast was effective as add-on therapy independent of LABA [139]. These observations were supported by the findings from a large Belgian open study including 5769 patients insufficiently controlled on ICS/LABA. Approximately 50% of the patients (n = 2442) were treated for concomitant rhinitis