New Pharmaceutical Agents In The Management Of Asthma

Kathryn Blake, Pharm.D.
Kathryn Blake, Pharm.D. is a Clinical Research Scientist with the Center for
Clinical Pediatric Pharmacology at Nemours Children's Clinic in Jacksonville.

Introduction

Since 1996, several new and important medications have been approved by the FDA for the treatment of asthma. The leukotriene modifiers, zileuton (Zyflo®, Abbott Laboratories) zafirlukast (Accolate®, Zeneca Pharmaceuticals), and montelukast (Singulair®, Merck and Co., Inc.), are the first new pharmacologic class of drugs for the treatment of asthma in over 20 years. Because these drugs are so new, it is not entirely clear where they should be used in the management of asthma although the National Asthma Education and Prevention Program guidelines¹ currently state that leukotriene modifiers can be considered for use to treat mild persistent asthma. Two new inhaled corticosteroids, fluticasone (Flovent® and Flovent Rotadisk®, Glaxo Wellcome, Inc.) and budesonide (Pulmicort Turbuhaler®, Astra Pharmaceuticals) provide certain advantages over older inhaled corticosteroids.

Leukotriene Modifiers

The leukotrienes interact with specific receptors found in various tissues including the lung.² Controlled administration of a leukotriene solution or aerosol to the airways elicits physiologic responses that mimic many of the inflammatory symptoms of asthma, including bronchoconstriction, airway hyperresponsiveness (an exaggerated bronchocon-strictive response to physical, chemical, and pharmacologic stimuli such as cold air, exercise, allergens, viral infection, and certain chemicals), increased microvascular permeability leading to edema, leukocyte activation, eosinophilia, and enhanced mucus secretion.^3,4 Leukotrienes are formed when the enzyme 5-lipoxygenase (5-LO), in conjunction with the co-factor 5-lipoxygenase-activating protein (FLAP), metabolizes arachidonic acid. An unstable intermediate product (LTA₄) is initially formed. Further conversion occurs to derive either the cysteinyl leukotrienes (cysLTs) LTC₄, LTD₄, and LTE₄, (formerly known as the slow reacting substances of anaphylaxis) or via a separate pathway, to form LTB₄ (Figure 1).⁴ LTC₄, LTD₄, and LTE₄ are highly potent inducers of airway smooth muscle contraction. The bronchoconstriction produced by LTD₄ has been estimated at 1000 to 10,000 times greater than the activity of histamine.⁴ LTC₄ and LTD₄ have approximately equal potency, however LTE₄ is approximately only 10% as potent as LTC₄ and LTD₄.⁴ LTC₄ is rapidly (minutes) converted to LTD₄, which is then converted to LTE₄ over approximately 30 minutes.⁵ Most LTE₄ is excreted within 4 hours and can be recovered in the urine and serve as a marker for leukotriene activity.⁶ LTC₄, LTD₄, and LTE₄ act by binding to a common receptor, CysLT₁, however, because LTD₄ is extremely potent and has the longest half-life of the leukotrienes, it has been the focus of anti-mediator drug development in asthma. Leukotriene modifiers block leukotriene mediated effects, either by preventing the enzymatic conversion of arachidonic acid to LTA₄, as with zileuton, or by blocking the binding of leukotrienes to the CysLT₁ receptor site, in the case of zafirlukast and montelukast.

Figure 1. Biochemical pathways of the formation and action of the leukotrienes and sites of action of leukotriene-modifying drugs. Reproduced with permission from Reference 4.

The leukotriene modifiers are administered orally (tablets) and currently only montelukast is available as a chewable tablet (and at a lower dose) for children. The pharmacokinetics differ significantly between zileuton, zafirlukast, and montelukast. Zileuton is dosed four times daily, zafirlukast twice daily, and montelukast once daily. Montelukast should be dosed at bedtime in order to provide the highest serum concentrations of montelukast during the night and early morning hours when asthma symptoms tend to be worse. Only montelukast is approved for use in children as young as 6 years of age. Zafirlukast bioavailability is significantly reduced by concomitant food ingestion and therefore must be dosed 1 hour before or 2 hours after a meal. Drug interactions occur with zileuton and zafirlukast but to date have not been found with montelukast. Zileuton decreases the clearance of warfarin, theophylline, and propranolol and dosages of these drugs will need to be reduced and careful patient monitoring should occur. Similarly, zafirlukast decreases the clearance of warfarin, corticosteroids, theophylline (rare cases reported), and possibly other drugs metabolized by the cytochrome P450 2C9 isoenzyme such as, tolbutamide, phenytoin, and carbamazepine.⁷ See Table 1 for a summary of these differences.

The adverse effects profile also differ between the leukotriene modifiers. Zileuton can cause liver dysfunction and liver function monitoring is currently recommended before beginning therapy and every month for the first 3 months and every 3 months for the next 9 months. Reports of Churg Strauss Syndrome, characterized by eosinophilia, pulmonary infiltrates, and myocardial dysfunction, have occurred in patients treated with zafirlukast and montelukast who were being weaned from oral corticosteroid therapy. It is believed that this syndrome is unmasked by the withdrawal of oral corticosteroid therapy rather than being caused by zafirlukast and montelukast as the syndrome also has been observed after treatment with inhaled corticosteroids during oral corticosteroid withdrawal.⁷

The leukotriene modifiers are effective in lessening the fall in pulmonary function caused by exposure to allergen or exercise. After allergen inhalation, these drugs attenuate the fall in FEV₁ (the volume of air expelled within the first second of forced expiration after maximal inhalation) by approximately 50% after a single dose but are not effective in preventing the increased airway hyperresponsiveness which occurs 24 hours later. Similarly, these drugs attenuate the fall in FEV₁ after exercise after a single dose by 50% to 80% but significant bronchospasm (as much as a 15% to 20% fall in FEV₁) can still occur when the patient exercises at the end of a dosing interval.^8,9 No studies have been performed evaluating the effect on exercise at the time of peak serum concentration. Leukotriene modifiers are not appropriate for prophylaxis prior to exercise and inhaled b₂-agonists remain the treatment of choice. However, they may moderate a patient's response to exercise when used chronically for asthma treatment.

Clinical trials indicate that therapy with leukotriene modifiers can improve pulmonary function by approximately 10% to 12%, reduce "as needed" inhaled b₂-agonist use by 30%, and decrease the number of nights per week that a patient wakes up due to asthma by 30%.⁴ Improvements may be noted as soon as one day of dosing and a trial of only 7 to 14 days is needed to determine if a patient will respond to leukotriene modifier monotherapy. However, in these studies, significant asthma symptoms (continued daily symptoms and daily as needed b₂-agonist use in some patients) remained when leukotriene modifiers were used as monotherapy. Most published clinical trials, however, evaluated these drugs in patients with moderate to severe persistent asthma, therefore, it is not surprising that these drugs did not provide complete control of asthma symptoms. Controlled clinical trials have not yet been conducted in patients with mild persistent asthma, the population for which complete control of symptoms might be achieved.

These drugs are less effective when compared with low-dose inhaled corticosteroid therapy (beclomethasone 400mg/day), however, some patients will achieve significant improvement in pulmonary function comparable to that obtained with inhaled corticosteroids.¹⁰ At this time, it is not possible to predict which patients are likely to have a significant response to leukotriene modifier therapy. Several studies have compared adding a leukotriene modifier to low dose inhaled corticosteroid therapy versus doubling the dose of inhaled corticosteroid.^11,12 These studies indicate comparable improvements in pulmonary function and asthma symptoms between the two treatment strategies. Another study has shown that adding a leukotriene modifier to inhaled corticosteroid therapy permits reduction in the dose of the inhaled corticosteroid while maintaining the same level of asthma control.¹³

These drugs currently have no role in the treatment of acute asthma and their role in the management of persistent asthma is being defined. The National Asthma Education and Prevention Program guidelines¹ currently recommend leukotriene modifiers as single drug therapy in the treatment of mild persistent asthma (patients who have symptoms more than twice a week but less than once a day) as an alternative after considering therapy with inhaled corticosteroids, cromolyn, or nedocromil. It may be reasonable to add a leukotriene modifier to therapy in patients who are receiving high doses of inhaled corticosteroids and reduce the dose of inhaled corticosteroid thus minimizing the risk of adverse effects of inhaled corticosteroids from long-term use. In addition, recent studies indicate that patients prefer, and are more adherent with, oral versus inhaled therapy for asthma.^14,15 Therefore, while inhaled corticosteroids are more effective than leukotriene modifiers in controlling asthma symptoms (at least in the conditions of a clinical trial), the leukotriene modifiers may have similar or better effectiveness in "real life" simply because patients are more willing to take an oral medication than an inhaled medication for asthma treatment.

Inhaled Corticosteroids

Inhaled corticosteroids are the most effective anti-inflammatory therapy available for providing long-term-control of asthma symptoms. The National Asthma Education and Prevention Program guidelines recommend the use of inhaled corticosteroids in all asthma patients who have symptoms more than twice a week. Because this includes most of the patients with asthma who come to a physician for asthma treatment, it is important that these medications are effective and safe and importantly, are as easy to use for the patient as possible. Fluticasone and budesonide are two inhaled corticosteroids that have become recently available. Both drugs have advantages over previously available inhaled corticosteroids including enhanced potency with fluticasone, fewer inhalations per day required for dosing, and availability as dry powder inhalers (DPI) (Flovent ® Rotadisk® and Pulmicort Turbuhaler®). DPIs may be easier for some patients to use compared with the coordination required to effectively use a metered-dose inhaler (MDI). Dry powder inhalers are being developed primarily because chlorofluorcarbons, which deplete the ozone layer, are being phased out of production. All metered-dose inhalers currently available (except Proventil HFA®) use chloroflurocarbons as the propellant.

Fluticasone is considerably more potent than other inhaled corticosteroids and the following relative potency has been established:¹⁶ fluticasone (Flovent®) > budesonide (Pulmicort®) = beclomethasone (Beclovent®, Vanceril®) > triamcinolone (Azmacort®) = flunisolide (Aerobid®). These differences in potency mean that larger doses of less potent inhaled corticosteroids will be required in order to achieve the same effect as lower doses of more potent inhaled corticosteroids (Table 2). Currently published data indicates that all the inhaled corticosteroids have the same potential efficacy as long as a sufficient dose is prescribed.

The effect of inhaled corticosteroids on the growth of children has recently received much attention in the lay press and professional journals. In July 1998, after review of both published and unpublished data evaluating the effect of inhaled corticosteroids on pediatric growth rate, the Food and Drug Administration (FDA) determined that a clinically relevant growth slowing does occur and issued (in November 1998) a requirement that new product labeling be applied to inhaled and intranasal corticosteroids used for allergy and asthma.¹⁷ A statement in the Precautions, Pediatric Use section now includes information about the possibility of growth suppression in children. A recent review on this topic states that low doses (Table 2) of inhaled corticosteroids does not impair growth in the majority of children.¹⁸ However, it is prudent to monitor the growth rate of all children on inhaled corticosteroids with a calibrated stadiometer in order to recognize any delays in growth before clinically significant changes occur. Moderate doses given on a regular basis can suppress growth rate by 1-1.5 cm/yr and it is not yet known if children who are growth suppressed over many years will achieve their final adult height. Low doses of budesonide, 100-200mg/day for 3 to 5 years, and fluticasone, 200 mg/day (from the Rotadisk®) for 1 year, have been shown not to affect growth rate in children.^18,19

Dry powder inhalers are breath-actuated devices which allow for inhalation of medication in the form of a dry micronized powder. Because they are breath-actuated minimal coordination is needed, however a change in inhalation technique (as compared to the MDI) is necessary. With DPIs, deep and forceful inspiration >60 L/minute ( £30 L/minute for MDIs) is required for optimal pulmonary drug delivery.^20,21 However, the Flovent® Rotadisk® delivers the correct dose at an inspiratory flow rate of at least 60 L/min and adults are able to generate a flow rate of 88 to 159 L/min and children ages 4 to 11 years, 43 to 175 L/min (Package Insert). A continuing concern is whether young children or acutely obstructed asthmatics can generate enough inspiratory flow to actuate DPIs. However, breath-actuated DPIs are under development which disperse drug at inspiratory flow rate of 15 L/min. The type of device such as, a metered dose inhaler, metered dose inhaler with a spacer, metered dose inhaler with the hydrofluoralkane propellant (non-CFC containing), and dry powder inhaler, can have clinically significant differing effects on the amount of drug delivered to the lung and the amount that gets absorbed systemically. The increased inspiratory flow required with DPIs and their inability to be used with spacers likely increases oropharyngeal drug deposition. This along with increased pulmonary drug deposition and absorption may increase the risks for topical and systemic adverse effects from medications, particularly corticosteroids if the dosage is not reduced. These issues are currently being addressed in clinical trials. Drug aggregation due to high humidity has largely been overcome by use of lactose fillers and the potential for provoking cough has not been widely reported.²²

Fluticasone is available in 3 dosage strengths in both the MDI and DPI. The purpose of having 3 strengths is to avoid having to prescribe a dose greater than approximately 2 puffs twice daily because it is known that the more times per day a medication is prescribed the less adherent the patient is with the regimen. The Flovent® Rotadisk® is available as 30 disks each containing 4 blisters of the specified dosage strength. Patients must reload a new disk every day if the dose is two inhalations twice daily. A Flovent® Diskus® containing 60 doses is currently in development. Budesonide is available as a single strength but contains 200 doses in each Turbuhaler®. A single Turbuhaler® could provide enough doses to last as long as 2 to 6 months depending on the dose prescribed. Pulmicort Turbuhaler® has a red dot which appears when there are approximately 20 inhalations remaining in the canister. Budesonide has also been approved for once daily administration.

Recent data suggests that dosing an inhaled corticosteroid once daily between 3:00 PM and 5:30 PM is as effective in controlling asthma symptoms as giving the same total daily dose divided four times daily.^23,24 Such a strategy could improve adherence and effectiveness of inhaled corticosteroid therapy. Several ongoing clinical trials of investigational inhaled corticosteroids are including treatment arms which compare once daily dosing in the evening with twice daily dosing.

Summary

Three leukotriene modifiers are currently available for the treatment of asthma as monotherapy in patients with symptoms less frequently than once a day and as add-on treatment in patients with more severe asthma who are currently receiving inhaled corticosteroids. They may provide added protection against triggers such as exercise in patients who are already receiving inhaled corticosteroids. Little differences in clinical efficacy are apparent between zileuton (Zyflo®), zafirlukast (Accolate®) and montelukast (Singulair®) but significant differences exist in the pharmacokinetics, drug interactions, and adverse effects. Montelukast (Singulair®) offers once daily administration, has no currently known drug interactions, has few adverse effects, and is available in a chewable tablet formulation for children. For these reasons, it is the preferred leukotriene modifier in the treatment of asthma. Fluticasone (Flovent®) is the most potent inhaled corticosteroid currently available but published data suggests that all inhaled corticosteroids are similar in efficacy when used in sufficient doses. The latter provides a reason for selecting fluticasone or budesonide (Pulmicort®) over other available inhaled corticosteroids as both can produce significant therapeutic effects with relatively few inhalations administered once or twice daily.

REFERENCES

1. National Asthma Education and Prevention Program. Expert Panel Report 2: Guidelines for the diagnosis and management of asthma. Bethesda, MD. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, National Heart, Lung, and Blood Institute, publication no. 97-4051. April 1997.
2. Coleman RA, Eglen RM, Jones RL, Narumiya S, Shimizu T, Smith WL, et al. Prostanoid and leukotriene receptors: a progress report from the IUPHAR working parties on classification and nomenclature. Adv Prostaglandin Thromboxane Leukot Res. 1995; 23:283-285.
3. Henderson WRJ. The role of leukotrienes in inflammation. Ann Intern Med. 1994;121:684-697.
4. Drazen JM, Israel E, O'Byrne PM. Treatment of asthma with drugs modifying the leukotriene pathway. N Engl J Med. 1999; 340:197-206.
5. Dahlen SE, Kumlin M, Bjorck T, Raud J, Hedqvist P. Airway smooth muscle and disease workshop: leukotrienes and related eicosanoids. Am Rev Respir Dis. 1987;136:S24-S28
6. Maltby NH, Taylor GW, Ritter JM, Moore K, Fuller RW, Dollery CT. Leukotriene C4 elimination and metabolism in man. J Allergy Clin Immunol. 1990;85:3-9.
7. Deykin A, Israel E. Newer therapeutic agents for asthma. Dis Mon. 1999; 45:117-144.
8. Leff JA, Busse WW, Pearlman D, Bronsky EA, Kemp J, Hendeles L, et al. Montelukast, a leukotriene-receptor antagonist, for the treatment of mild asthma and exercise-induced bronchoconstriction [see comments]. N Engl J Med. 1998;339:147-152.
9. Kemp JP, Dockhorn RJ, Shapiro GG, Nguyen HH, Reiss TF, Seidenberg BC, et al. Montelukast once daily inhibits exercise-induced bronchocon-striction in 6- to 14-year-old children with asthma. J Pediatr. 1998;133:424-428.
10. Malmstrom K, Meltzer EO, Prenner B, Lu S , Weinstein S, Wolfe J, et al. Effects of montelukast (a leukotriene receptor antagonist), loratadine, montelukast + loratadine and placebo in seasonal allergic rhinitis and conjunctivitis. J Allergy Clin Immunol. 1998; 101:s97-s97 Abstract.
11. Nyak AS, Anderson P, Charous BL, Williams K, Simonson S. Equivalence of adding zafirlukast versus double-dose inhaled corticosteroids in asthmatic patients symptomatic on low-dose inhaled corticosteroids. J Allergy Clin Immunol. 1998; 101:S233 Abstract.
12. O'Connor BJ, Godard P, Dube LM, Swanson LJ. The effect of a 5-lipoxygenase inhibitor, zileuton, plus low-dose inhaled beclomethasone compared to higher dose beclomethasone alone in patients with asthma. Am J Respir Crit Care Med. 1996; 153:A803 Abstract.
13. Leff JA, Israel E, Noonan MJ, Finn AF, Godard P, Lofdahl CG, et al. Montelukast (MK-076) allows tapering of inhaled corticosteroids (ICS) in asthmatic patients while maintaining clinical stability. Am J Respir Crit Care Med. 1997; 155:A976 Abstract.
14. Kelloway JS, Wyatt RA, Adlis SA. Comparison of patients' compliance with prescribed oral and inhaled asthma medications. Arch Intern Med. 1994; 154:1349-1352.
15. Ringdal N, Whitney JG, Summerton L. Problems with inhaler technique and patient preference for oral therapy - tablet zafirlukast vs inhaled beclomethasone. Am J Respir Crit Care Med. 1998; 157:A416 Abstract.
16. Kelly HW. Comparison of inhaled corticosteroids. Ann Pharmacother. 1998; 32:220-232.
17. FDA requires new pediatric labeling for inhaled, intranasal corticosteroids [FDA Talk Paper November 9, 1998]. 1998; Bethesda, MD. Food and Drug Administration.
18. Allen DB. Influence of inhaled corticosteroids on growth: a pediatric endocrinologist's perspective. Acta Paediatr. 1998; 87:123-129.
19. Thorsson L, Edsbacker S, Conradson TB. Lung deposition of budesonide from Turbuhaler is twice that from a pressurized metered-dose inhaler P-MDI. Eur Respir J. 1994; 7:1839-1844.
20. Anonymous. Witek TJ, Schachter EN, editors. Pharmacology and Therapeutics in Respiratory Care. Philadelphia: W.B. Saunders Company. 1994; 72.
21. Newman SP. Delivery of drugs from the respiratory tract. In: Chung KF, Barnes PJ, editors. Pharmacology of the Respiratory Tract. New York: Marcel Dekker, 1993: 701-728.
22. Kamada AK. Therapeutic controversies in the treatment of asthma. Ann Pharmacother. 1994;28:904-914.
23. Pincus DJ, Szefler SJ, Ackerson LM, Martin RJ. Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J Allergy Clin Immunol. 1995;95:1172-1178.
24. Pincus DJ, Humeston TR, Martin RJ. Further studies on the chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J Allergy Clin Immunol. 1997; 100:771-774.

Jacksonville Medicine / November, 1999