Zafirlukast

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Abstract
Zafirlukast is a selective and competitive orally administered inhibitor of the cysteinyl leukotrienes LTC4, LTD4 and LTE4. The drug is indicated for the prophylaxis and treatment of chronic asthma, and has been developed in response to mounting evidence indicating the importance of the cysteinyl leukotrienes in the pathogenesis of this disorder. The efficacy of zafirlukast 20mg twice daily has been shown in double-blind placebo-controlled studies of up to 13 weeks’ duration in patients aged ≥12 years. Zafirlukast was consistently superior to placebo in improving objective measures of lung function and subjective measures such as symptom scores and use of as-required bronchodilator therapy. This dosage is also as effective when added to low-dosage inhaled corticosteroid therapy as doubling of corticosteroid dosages. Recent studies indicate superior efficacy over zafirlukast of twice-daily inhaled fluticasone propionate 88µg or salmeterol 42µg, although zafirlukast was nevertheless associated with clinical improvement. Data also show zafirlukast 40mg to be of similar efficacy to pranlukast 225mg (both twice daily). Overall, preliminary pharmacoeconomic data suggest that healthcare costs are reduced by zafirlukast therapy, although superior cost effectiveness has been reported with inhaled fluticasone propionate, and further studies are needed. Data are available to show improvements in patient-rated quality of life, and preference for and high rates of compliance with zafirlukast. In clinical trials, zafirlukast has shown an adverse event profile similar to that of placebo. Isolated reports of hepatic dysfunction in a small number of individuals receiving the drug have been received, and recommendations for monitoring of patients are in place. Although no causal relationship has been established between zafirlukast and Churg-Strauss Syndrome, patients undergoing corticosteroid dosage reductions require careful surveillance. Conclusions: zafirlukast is an effective and well tolerated agent for preventive monotherapy in mild to moderate persistent asthma. Emerging data indicate benefit of the drug when added to low-dosage inhaled corticosteroids and show that it may be a viable alternative to inhaled adjunctive treatments and increased corticosteroid dosages in some patients. Although inhaled fluticasone propionate and salmeterol have been associated with greater clinical improvement than zafirlukast in clinical studies, compliance considerations and the confirmed clinical efficacy relative to placebo of the drug denote zafirlukast as an effective alternative in treatment programmes based on individualised therapy. As experience with zafirlukast accumulates, it is expected that the drug will be positioned more definitively in national and international treatment guidelines. Zafirlukast is a selective and competitive inhibitor of the cysteinyl leukotrienes LTC4, LTD4 and LTE4. In humans, the drug prevents bronchoconstriction induced by LTD4, allergens, exercise, cold air, sulphur dioxide or platelet activating factor. Zafirlukast has also been shown to have a beneficial effect on airway inflammation induced by LTE4, and to attenuate late-phase bronchoconstrictive responses to allergenic challenge. The effect of the drug on bronchial hyper-responsiveness has not been fully clarified, although limited data suggest a smaller effect of zafirlukast than inhaled fluticasone propionate in this respect. Zafirlukast exhibits 2-compartment pharmacokinetic characteristics. Peak plasma concentrations are reached within 3 hours, and steady-state conditions are attained after 3 days of twice-daily oral administration. Coadministration with food reduces the rate and extent of absorption of the drug. Zafirlukast is approximately 99% bound to plasma proteins. The mean plasma elimination half-life of zafirlukast ranged from 8 to 16 hours in pharmacokinetic studies, and the drug is metabolised extensively in the liver by the cytochrome P450 (CYP) system. Elimination of zafirlukast, chiefly as metabolites, takes place predominantly via the faecal route. Inhibition by zafirlukast of the hepatic microsomal enzymes CYP2C9 and CYP3A gives rise to the potential for interactions with other drugs metabolised via these routes. Coadministration of zafirlukast with warfarin may result in increased prothrombin times, and careful monitoring with possible adjustment of warfarin dosages is required in patients so affected. Plasma concentrations of zafirlukast have been reduced in patients also receiving theophylline or erythromycin, and increased with coadministration of aspirin. Increases in plasma theophylline concentrations have not been reported in studies in patients who also received zafirlukast, although there have been isolated reports of increased serum/plasma concentrations of theophylline (occasionally with signs of theophylline toxicity) in patients on long term therapy who have had zafirlukast added to their medication. There have been no significant interactions reported with single doses of azithromycin or clarithromycin. Zafirlukast does not appear to affect oral contraceptive efficacy. The therapeutic efficacy of zafirlukast 20mg twice daily orally has been shown in a series of randomised and double-blind comparisons with placebo of up to 13 weeks’ duration. Zafirlukast was consistently superior to placebo in improving objective measures of lung function [forced expiratory flow in 1 second (FEV1) and morning and evening peak expiratory flow (PEF)] and subjective measures such as symptom scores and use of as-required bronchodilator therapy in patients with mild to moderate asthma. The drug has also shown efficacy in patients with severe persistent asthma, and data are available to show maintenance of benefit with long term use. Three double-blind placebo-controlled studies of 4, 6 and 10 weeks’ duration have been carried out in a total of 1193 children aged...

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