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Zafirlukast

A Review of its Pharmacology and Therapeutic Potential in the Management of Asthma

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Summary

Synopsis

Zafirlukast is a competitive and selective leukotriene receptor antagonist indicated for the prophylaxis and treatment of chronic asthma. The rationale for the development of leukotriene antagonists was based on in vitro and in vivo data demonstrating the extensive role of the cysteinyl leukotrienes C 4 (LTC4), D4 (LTD4) and E4 (LTE4) in the pathogenesis of asthma.

Initial data have demonstrated an improvement in pulmonary function and symptom control and a reduction in the use of short-acting inhaled β2-adrenoceptor agonist therapy in patients with mild to moderate asthma treated with oral zafirlukast at the recommended dosage of 20mg twice daily. Available data also suggest that zafirlukast may significantly reduce the incidence of asthma exacerbations.

Data on the comparative efficacy of zafirlukast and existing antiasthma medications are limited. Results from 2 double-blind randomised studies comparing zafirlukast 20mg twice daily with sodium cromoglycate aerosol or dry powder inhalation reported similar efficacy for both drugs. In a comparison with inhaled beclomethasone dipropionate (0.2 to 0.25mg twice daily), improvements in morning peak expiratory flow rate, forced expiratory volume in 1 second and daytime symptom score were significantly less with zafirlukast 20mg twice daily for 6 weeks. However, available data suggest that patient compliance and patient preference may be greater with oral zafirlukast 20mg twice daily than with twice-daily inhaled corticosteroid therapy.

Confounding results from 2 studies preclude any clear conclusions regarding the potential steroid-sparing effect of zafirlukast at the recommended dosage of 20mg twice daily. Furthermore, Churg-Strauss syndrome has been reported in 6 patients who were being withdrawn from oral corticosteroid therapy while receiving treatment with oral zafirlukast. It is, therefore, recommended that zafirlukast-treated patients who require a reduction in their oral corticosteroid therapy are closely monitored.

Zafirlukast is generally well tolerated. Reports of elevated liver enzymes in patients receiving high dosages of zafirlukast (80mg twice daily) preclude the use of dosages exceeding 40mg twice daily. Careful monitoring is necessary in zafirlukast-treated patients receiving concomitant therapy with drugs such as warfarin, terfenadine and erythromycin because of the potential for drug interactions.

Thus, zafirlukast is a potentially useful addition to current antiasthma therapies in patients with mild to moderate asthma. Because zafirlukast is administered orally, it may be particularly beneficial in patients poorly compliant with asthma therapy as a result of poor inhaler technique. Further investigation of the efficacy of zafirlukast is expected to more clearly define its position in the management of asthma.

Pharmacodynamic Properties

The cysteinyl leukotrienes C4 (LTC4), D4 (LTD4) and E4 (LTE4) are important inflammatory mediators clearly implicated in the pathogenesis of asthma. Zafirlukast is a competitive inhibitor of LTD4 and LTE4. In vitro, zafirlukast antagonised the contractile response of guinea-pig and human airway smooth muscle to LTD4 and LTE4 and competitively inhibited the binding of LTD4 and LTE4 to guinea-pig lung parenchymal membrane. Zafirlukast is selective for cysteinyl leukotriene receptors and demonstrated minimal affinity for a variety of other receptor types, including α- and β-adrenoceptors and muscarinic receptors in isolated tissue.

In vivo, zafirlukast antagonised the pulmonary effects of LTC4 and LTD4 and showed potential anti-inflammatory activity in guinea-pig airways with inhibition of the eosinophil chemotactic responses to LTC4, LTD4 and LTE4 and a reduction in LTD4-induced oedema.

Bronchial challenge studies in humans have demonstrated the protective efficacy of oral zafirlukast against bronchoconstriction induced by various stimuli, including LTD4, exercise and cold air. Similarly, oral administration of zafirlukast showed protective efficacy relative to placebo against the early and late bronchoconstrictive response to allergen challenge. Zafirlukast has also been reported to reduce cellular infiltration into the airways after allergen challenge. However, further investigations are necessary to clearly determine the extent of the protection conferred by zafirlukast against increased bronchial hyperresponsiveness associated with the late phase response.

Pharmacokinetic Properties

The pharmacokinetics of zafirlukast are best described by a 2-compartment model. Maximum plasma concentrations (Cmax) were achieved 3 hours after single-dose oral administration of zafirlukast 20 or 40mg to healthy volunteers. The absolute bioavailability of zafirlukast is unknown; however, coadministration with food produced an approximately 40% reduction in the bioavailability of the drug. The drug binds extensively to plasma proteins (>99%), predominantly to albumin and has a mean terminal elimination half-life of approximately 10 hours in both healthy volunteers and patients with asthma.

Zafirlukast undergoes extensive hepatic metabolism. Hydroxylation by cytochrome P450 CYP2C9 is the major biotransformation pathway for the drug. The metabolites of zafirlukast appear to contribute little to its overall activity. The faeces are the main route of elimination, with urinary excretion accounting for <10% of an orally administered dose.

Because hepatic metabolism is extensive, clearance of zafirlukast is reduced in patients with hepatic impairment. In patients with stable alcoholic cirrhosis, the Cmax and area under the plasma concentration-time curve for zafirlukast were increased by 50 to 60% compared with healthy volunteers.

Inhibition of the cytochrome P450 CYP2C9 and CYP3A isoenzymes by zafirlukast has been reported in vitro. Because there is the potential for drug interactions to occur with other agents which compete for these enzymes, appropriate clinical monitoring is required when zafirlukast is coadministered with these agents. Zafirlukast interacts with warfarin to produce a clinically significant increase in prothrombin time but it does not significantly alter the pharmacokinetic profile of terfenadine carboxylate, the active metabolite of terfenadine. Plasma concentrations of zafirlukast decreased when the drug was administered concomitantly with erythromycin, theophylline or terfenadine and increased when it was coadministered with aspirin.

Therapeutic Potential

The therapeutic efficacy of oral zafirlukast has been investigated in patients aged ≥12 years with predominantly mild to moderate asthma. Most studies evaluated zafirlukast 20mg twice daily for up to 13 weeks and included both an objective assessment of pulmonary function and a subjective assessment of symptom control as a measurement of therapeutic efficacy. Although many of the investigations included large patient numbers (n > 100), most of the data from these studies are available in abstract form only.

In double-blind randomised studies, oral zafirlukast 20mg twice daily generally produced significantly greater improvements in asthma symptom scores, nocturnal awakenings, forced expiratory volume in 1 second (FEV1) and peak expiratory flow (PEF) than placebo and significantly reduced the need for as-required short-acting inhaled β2-adrenoceptor agonist therapy. Favourable quality-of-life benefits were also reported in 1 study during treatment with zafirlukast 20mg twice daily for 13 weeks. In a meta-analysis of 5 double-blind placebo-controlled multicentre trials comparing zafirlukast (4 to 80mg twice daily) with placebo, zafirlukast also significantly reduced the incidence of asthma exacerbations.

Comparative data on the efficacy of zafirlukast and other antiasthma medications are limited. Zafirlukast 20mg twice daily has been compared with sodium cromoglycate aerosol (1.6mg 4 times daily) or dry powder inhalation (40mg daily) in patients with mild to moderate asthma in 2 double-blind randomised studies. Neither study demonstrated a significant difference between the 2 treatments in terms of pulmonary function or symptom control and 1 study showed no overall significant benefit with the active drugs compared to placebo in patients with mild asthma. In a comparison with inhaled beclomethasone dipropionate therapy (0.2 to 0.25mg twice daily for 6 weeks), improvements in morning PEF, FEV1 and daytime symptom score were significantly less with zafirlukast 20mg twice daily. However, initial results suggest that patient preference and compliance may be greater with oral zafirlukast 20mg twice daily than with twice-daily inhaled corticosteroid therapy.

Because of confounding results from 2 studies, no clear conclusions can be drawn regarding the potential steroid-sparing effect of zafirlukast 20mg twice daily. In another investigation, concomitant treatment with high-dose zafirlukast therapy (80mg twice daily), which is outside recommended treatment guidelines, was associated with a significant improvement in pulmonary function and symptom control in patients with moderate to severe asthma who were symptomatic despite receiving high-dose inhaled corticosteroid therapy.

Pharmacoeconomic Considerations

Treatment with zafirlukast 20mg twice daily plus as-required short-acting inhaled β2-adrenoceptor agonist therapy was more effective clinically and associated with a marked reduction in the use of healthcare resources (number of healthcare contacts, absenteeism from school or work, use of inhaled β2-adrenoceptor agonist therapy and non-asthma medication) compared with placebo plus as-required β2-adrenoceptor agonist therapy. Furthermore, considerable cost savings have also been demonstrated for patients treated with zafirlukast compared with placebo as a result of a reduction in the incidence of asthma exacerbations leading to study withdrawal. However, well designed pharmacoeconomic studies that compare zafirlukast with other antiasthma drugs are necessary before the potential benefit of zafirlukast can be fully evaluated in economic terms.

Tolerability

According to data from 7761 patients recruited to controlled clinical trials, the profile and incidence of adverse events were similar among patients treated with short term (≤20 weeks) zafirlukast therapy (n = 5188; typically 20mg twice daily) or placebo (n = 2573). The most frequent adverse events associated with zafirlukast therapy were pharyngitis (16%), headache (12%) and worsening of asthma (8%). Other adverse events including infection, rhinitis, flu syndrome, nausea and cough developed in 3 to 4% of patients. Longer term zafirlukast therapy (21 weeks to >2 years; n = 1120) was associated with a similar profile but a higher incidence of adverse events (pharyngitis 46%, worsening of asthma 28%, headache 16%, infection 16%, flu syndrome 10% and rhinitis 8%) than over the short term. The incidence of serious adverse events during long term therapy was low, the most frequent being worsening of asthma (1.5%) and infection (0.8%).

Infrequent asymptomatic elevations in serum liver enzymes have been reported with high dosages of zafirlukast (80mg twice daily). These elevations returned to normal after cessation of therapy. However, because of these findings, the administration of zafirlukast dosages exceeding 40mg twice daily is not recommended.

Postmarketing surveillance studies have revealed a very small number of cases of Churg-Strauss syndrome (n = 6) in patients who were being withdrawn from oral corticosteroid therapy while receiving treatment with zafirlukast.

Dosage and Administration

In the prophylaxis and treatment of asthma, the recommended oral dosage regimen for zafirlukast is 20mg twice daily. Dosage guidelines are currently unavailable for the use of zafirlukast in children aged <12 years. Zafirlukast should be administered at regular intervals and should not be taken with food.

Because zafirlukast is excreted in breast milk, the drug should not be administered to women who are breast feeding. Furthermore, zafirlukast should not be used during pregnancy. Dosage reductions for zafirlukast do not appear to be necessary in the elderly or in patients with renal impairment. However, dosage modification may be necessary in patients with hepatic impairment, although specific dosage recommendations have yet to be devised for this patient group. If a patient experiences symptoms of liver dysfunction, medical attention should be sought immediately. Because of a small number of reports of Churg-Strauss syndrome in zafirlukast-treated patients in association with a reduction in oral corticosteroid dosage, individuals who require tapering of their oral corticosteroid dosage while receiving treatment with zafirlukast should be monitored closely.

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Correspondence to Julie C. Adkins.

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Various sections of the manuscript reviewed by: N.C. Barnes, Department of Respiratory Medicine, The London Chest Hospital, London, England; L-P. Boulet, Centre de Pneumologie de l’Hôpital Laval, Sainte-Foy, Quebec, Canada; F. Chung, Department of Thoracic Medicine, National Heart and Lung Institute, London, England; J.W. de Jong, University Hospital Groningen, Groningen, The Netherlands; Z. Diamant, Leiden University Medical Centre, Leiden, The Netherlands; R.F. Lockey, Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida, USA; K. McGill, Department of Medicine, University of Wisconsin-Madison Medical School, Madison, Wisconsin, USA; R. Pauwels, University Hospital Department of Respiratory Diseases, Ghent, Belgium; A.P. Sampson, Immunopharmacology Group, Southampton General Hospital, Southampton, England; L.J. Smith, Pulmonary Division, Northwestern University Medical School, Chicago, Illinois, USA; D.S. Theodoropoulos, Division of Allergy and Immunology, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida, USA; S. Wenzel, National Jewish Medical and Research Center, Denver, Colorado, USA.

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Adkins, J.C., Brogden, R.N. Zafirlukast. Drugs 55, 121–144 (1998). https://doi.org/10.2165/00003495-199855010-00008

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