Chest
Volume 111, Issue 2, Supplement, February 1997, Pages 52S-60S
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Worldwide Clinical Experience With the First Marketed Leukotriene Receptor Antagonist

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Pranlukast (SB 205312, ONO-1078) is an orally active, potent, selective blocker of peptidyl-leukotriene receptors. Pranlukast has been studied in a worldwide clinical development program and recently was approved in Japan for the treatment of asthma. This worldwide experience includes a pivotal safety and efficacy study conducted in Japan, a leukotriene D4 (LTD4) challenge study conducted in Europe, and two safety, tolerability, and clinical activity studies conducted in Europe and North America. The pivotal study was a randomized, double-blind, 8-week comparison of pranlukast, 225 mg bid, and azelastine, 2 mg bid. Improvements in asthma symptom scores, morning and evening peak expiratory flow rate (PEFR), and a decreased need for bronchodilators and corticosteroids in the pranlukast-treated group were statistically significant when compared with those in the azelastine-treated group. The most common adverse experiences were GI. The European challenge study evaluated the ability of 5-day therapy with pranlukast, 450 mg bid, to block the bronchoconstrictor effect of inhaled LTD4. A single dose of pranlukast resulted in a 10.6-fold increase in the concentration of LTD4 required to produce a 35% decrease in specific airways conduction; following 5 days of therapy, this increased to 25.9-fold. The two safety, tolerability, and clinical activity studies were randomized, double-blind, placebo-controlled, 4-week evaluations of pranlukast, 225 to 450 mg bid. Improvements in FEV1, PEFR, and asthma symptoms were noted. Ongoing studies will define further the role of pranlukast as a treatment for asthma and allergic rhinitis.

Section snippets

PRANLUKAST CLINICAL DEVELOPMENT PROGRAM—INITIAL CLINICAL STUDIES CONDUCTED IN JAPAN

The initial challenge studies and clinical safety and efficacy studies of pranlukast in the treatment of asthma conducted in Japan documented the activity of single and repeated doses in attenuating immediate and late airway responses to various provocations.14, 15, 16 Doses of pranlukast ranging from 150 to 900 mg were studied; the most common dosage used was 225 mg bid. Studies lasted from 4 to 36 weeks.

Data reported in the pivotal study of pranlukast vs azelastine are representative of data

PRANLUKAST CLINICAL DEVELOPMENT PROGRAM—EXPANSION INTO EUROPE AND NORTH AMERICA

As the clinical development program for pranlukast expanded into Europe and North America, the need to redefine the optimal dosage range for pranlukast was recognized. European and North American patients differ from Japanese patients in body surface area and body weight. Accordingly, an LTD4 challenge study conducted in Europe used higher dosages and repeated-dose administration of pranlukast (450 mg bid for 5 days).17 In addition, phase 2B studies were conducted in Europe and North America to

STUDIES IN SEASONAL ALLERGIC RHINITIS

As noted, researchers have found that leukotrienes play a critical role as inflammatory mediators throughout the upper and lower airway.1, 2, 3, 4, 5, 6, 7, 8 Because of this, researchers and clinicians have begun to view inflammatory airway disease—including asthma and allergic rhinitis—as a continuum of inflammation rather than as separate, distinct diseases. Consistent with this evolving perspective, pranlukast is being evaluated not only as a novel treatment for asthma but also as a

CONCLUSIONS

Considerable experience has been gained with pranlukast worldwide, and the data generated so far on its clinical pharmacology, efficacy, and safety indicate that LTRAs such as pranlukast hold great promise as important therapeutic advances in the treatment of patients who have inflammatory airway disease. Recent challenge studies conducted in Europe and North America have built on the wealth of experience already available in Japan and have found that pranlukast inhibits bronchoconstriction due

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