Anti-leukotriene drugs - clinical applications

Summary
Two leukotriene receptor antagonists, montelukast and zafirlukast, have been approved for use in Australia. These drugs afford a degree of protection against antigen challenge and exercise-induced bronchospasm. They are particularly effective for patients with asthma who are sensitive to aspirin. While regular use can control asthma, they are no more effective than 400 microgram/day of beclomethasone dipropionate. Montelukast and zafirlukast are oral preparations. They may be useful for patients who prefer tablets or cannot tolerate inhaled beclomethasone because of local adverse effects.

Introduction
The discovery of a slow reacting substance (SRS) was made at the Walter and Eliza Hall Institute in Melbourne in 1938. It has taken 60 years of investigation, drug development and clinical trials to identify clinically useful anti-leukotriene drugs. Two of these drugs (montelukast and zafirlukast) have recently been approved for use in Australia.

Types of anti-leukotriene drugs
Four classes of drugs that interfere with leukotriene synthesis or activity have been developed. To date, no significant clinical differences have been observed between drugs of these classes, so the term anti-leukotriene drug has been coined for these compounds.

The 5-lipoxygenase inhibitors block the activity of 5-lipoxygenase. The 5-lipoxygenase activating protein (FLAP) inhibitors displace arachidonic acid from its binding site on the FLAP molecule and prevent this substrate from being presented to 5-lipoxygenase. These two classes of drugs block the synthesis of both cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) and LTB₄. The third class of drugs (to which the currently available drugs in Australia belong) is the cysteinyl leukotriene receptor antagonists. The fourth class is the LTB₄ receptor antagonists.

Efficacy in acute challenge

LTD₄-induced bronchoconstriction
In a study of mild asthmatics, a 10-fold shift in the LTD₄ dose-response curve was evident 12 hours after an oral dose of zafirlukast 40 mg. That is, higher doses of LTD₄ were required to induce bronchospasm because zafirlukast blocked the bronchoconstrictor response to LTD₄. The patients who had higher plasma concentrations of the drug at 12 hours had greater shifts in their dose-response curves than patients with lower plasma concentrations. A similar response was observed in studies of montelukast.

Exercise challenge
Exercise-induced asthma is partially inhibited by anti-leukotriene drugs. Zafirlukast, 20 mg taken orally two hours before exercise, had variable efficacy, ranging from complete protection in some individuals to little or no protection in others. The mean maximum percent falls in FEV₁ after exercise were 36% for placebo and 21.6% for zafirlukast. Montelukast (10-50 mg) ameliorated asthma when the exercise challenge was performed at the end of the once daily dosing interval, immediately before the next dose. The protective effect of the anti-leukotriene drugs is less than that of the inhaled beta agonists, which abolish exercise-induced asthma in the majority of patients.

Antigen challenge
A challenge with inhaled antigens causes an early asthmatic response, peaking at 15 minutes with recovery over the next hour or so. In about 50% of patients, this early asthmatic response is followed after 6-8 hours by a late asthmatic response. This late reaction is accompanied by swelling of the airway wall and infiltration by inflammatory cells, together with increased airway response to methacholine and histamine (i.e. increased airway reactivity).

Zafirlukast (40 mg) given two hours before antigen challenge attenuates the early response by 80% and the late response by 50%. It partially reduces the associated increase in airway reactivity 6 hours after the challenge. In another study, a single 40 mg oral dose of zafirlukast reduced the response to inhaled cat allergen compared to placebo.

There was considerable inter patient variability in these studies. This variability in effectiveness is probably not due to pharmacokinetic differences. There may well be heterogeneity in the relative importance of leukotrienes in the pathogenesis of asthma in different people.

Some studies have used a bronchoscope to deliver an allergen challenge to a lung segment. The patients took zafirlukast 20 mg twice daily for 5 days before the challenge. Bronchial fluid was then collected 5 minutes and 48 hours after the antigen challenge. After 5 minutes, there were no statistically significant differences, in cell counts in the broncho-alveolar lavage fluid, between zafirlukast and placebo. By 48 hours, the basophil and lymphocyte counts and the histamine concentrations were reduced in the patients given zafirlukast. Studies of this type provide direct evidence that the oral administration of anti-leukotriene drugs reduces the magnitude of the lung's inflammatory response to an antigen challenge.

Airway hyper reactivity
Allergen-induced hyper reactivity may be an important mechanism in the continuing symptoms and progression of disease. The ability of drugs to prevent this effect would be an important component of long-term drug therapy. Zafirlukast has been found to attenuate the antigen-induced increase in hyper reactivity, but similar studies with montelukast have not been reported. Oral treatment with pranlukast (not available in Australia) for 5 days also attenuates the allergen-induced hyper reactivity suggesting that this is a class effect.

Routes of administration
Most of the currently available asthma therapies are inhaled. This delivers the drugs more effectively to target sites in the lung and reduces the risk of systemic activity. The inhaled route of administration does have some problems, particularly with non-compliance or poor inhalation technique. Montelukast and zafirlukast have been developed as oral formulations, largely because of patient preference for this type of medication in the world's two largest asthma markets, the U.S.A. and Japan. While tablets eliminate the problem of variable dose delivery due to poor inhalation technique, their systemic bioavailability may increase the risk of adverse events.

Pharmacokinetics
Zafirlukast is well absorbed with a mean oral bioavailability of 80%. Peak plasma concentrations are achieved by 2-3 hours and the plasma half-life is approximately 10 hours. Montelukast has a mean oral bioavailability of approximately 65%. Peak plasma concentrations are achieved by 2-3 hours and the plasma half-life is 5-6 hours. Both drugs undergo liver metabolism to several products that are thought to be inactive.

Use in chronic asthma
Large-scale clinical trials have studied zafirlukast (20 mg twice daily) in patients with mild asthma requiring treatment with beta agonists only. Compared with placebo, patient-reported endpoints, such as daytime asthma scores, night wakenings and use of beta agonists, have improved with zafirlukast.

In another large clinical trial, montelukast 10 mg daily was compared with placebo in patients who usually only used beta agonists for their mild asthma. In this study, there was an increase in FEV₁, quality of life and parental global evaluation. In these trials, montelukast decreased the eosinophil counts in blood and in sputum.

Comparison with other drugs
In a 13-week comparative trial between zafirlukast 20 mg twice daily and sodium cromoglycate (1600 microgram daily), both drugs reduced symptom scores and improved lung function compared with placebo. Direct comparison with inhaled corticosteroids shows that both zafirlukast and montelukast are no more potent than beclomethasone dipropionate 400 microgram daily.

A 6-week double-blind study randomised patients with mild to moderate asthma to take beclomethasone dipropionate 200-250 microgram or zafirlukast 20 mg or 80 mg. Each drug was taken twice daily. Neither dose of zafirlukast was as effective as beclomethasone dipropionate. The most revealing finding in this study was the fact that there was a significant proportion of patients who did not respond to inhaled corticosteroids and a similar proportion who did not respond to zafirlukast. As there were 3 parallel treatment groups, there was no crossover to determine if the patients who did not respond to steroids may respond to the anti-leukotriene drugs. Such studies will be important in determining where the anti-leukotriene drugs fit in the treatment of asthma.

Aspirin-sensitive asthma
A small minority of asthmatic patients (2-5%) cannot tolerate aspirin. It can induce bronchospasm, naso-ocular and gastrointestinal reactions. These patients have an abnormally high leukotriene production, as measured by urinary LTE₄. An aspirin challenge further increases the LTE₄ concentration. Several studies have shown that the anti-leukotriene drugs diminish the bronchoconstrictor response in patients with aspirin-sensitive asthma.

Steroid sparing effect
In a randomised, double-blind, placebo-controlled trial of 79 patients with asthma requiring inhaled beclomethasone (1500 microgram daily or more), the inhaled dose of beclomethasone dipropionate was halved. The patients were then randomised to take pranlukast (not available in Australia) or placebo for 6 weeks.¹ In the placebo group, there was a decrease in FEV₁ and morning and evening peak flows. In contrast, these measures remained above baseline values (those recorded before randomisation) in patients taking pranlukast. The use of this leukotriene receptor antagonist had allowed a reduction in inhaled corticosteroids.

In another study, patients with stable asthma treated with 400-750 microgram of beclomethasone dipropionate were randomised to treatment with zafirlukast 20 mg twice daily or placebo. Both placebo and treated groups were able to reduce their dose of inhaled corticosteroids without loss of control of asthma. There was no statistical difference between the groups with respect to daytime symptoms, daily use of beta₂ agonist or morning peak flows at the end of the study.

Adverse effects
Montelukast has been generally well tolerated in clinical trials. The adverse effects that have been reported more frequently than placebo in these clinical trials include abdominal pain and headache. Zafirlukast may cause drug interactions because it inhibits cytochrome P450, e.g. doses of warfarin may need to be reduced. Both erythromycin and theophylline reduce the plasma concentrations of zafirlukast by approximately 30-40%.

A rare disorder called Churg Strauss syndrome has occurred in 8 patients treated with zafirlukast.² It is characterised by blood eosinophilia and eosinophilic infiltration of various organs, including skin and lung. The precise mechanism for this phenomenon is unclear, but it has been proposed that the patients had a primary eosinophilic disorder which was unmasked by the cessation (or reduction in one case) of corticosteroids when the patients began treatment with zafirlukast. Vigilance is necessary to determine if this syndrome occurs with other anti-leukotriene drugs.

Where do anti-leukotriene drugs fit?
The majority of trials showing clinical efficacy of anti-leukotriene drugs have studied patients with mild asthma, requiring only beta₂ agonists. In these patients, the drugs are no more effective than 400 microgram beclomethasone dipropionate.³ The anti-leukotriene drugs may have a role in patients whose asthma would be controlled with modest doses of inhaled corticosteroids, if they were unable to tolerate the local adverse effects. The oral drugs may also be useful in patients who comply poorly with inhaler devices or have difficulty using an inhaler. Oral medications may also be useful in children, although neither montelukast nor zafirlukast is currently approved in Australia for use in children under 6 years of age. Current evidence suggests that the anti-leukotriene drugs are likely to be effective in some individuals whose asthma is much more dependent upon leukotriene generation than others e.g. aspirin-sensitive asthma.

It is premature to state that the anti-leukotriene drugs are genuinely `steroid sparing'. If clinical trials to specifically address this question show that this is the case, then these drugs could be used in a similar fashion to long-acting beta agonists to cap the dose of inhaled corticosteroids.

In Australia, we have a tradition of prescribing inhaled medications for the treatment of asthma. With the advent of the orally effective anti-leukotriene drugs, we now have an alternative approach to prescribing regular therapy. When prescribing these drugs, we must be mindful of the possibility of drug interactions because zafirlukast has the potential to affect (or be affected by) the hepatic metabolism of several other drugs.