Inhibition of the early asthmatic response to inhaled allergen by the 5-lipoxygenase activating protein inhibitor GSK2190915: a dose–response study

Abstract

BACKGROUND: GSK2190915, a 5-lipoxygenase activating protein inhibitor, inhibits the production of cysteinyl leukotrienes and leukotriene B4 and 5-oxo-6,8,11,14-eicosatetraenoic acid. We have previously reported that GSK2190915 100 mg daily inhibits early and late asthmatic responses to inhaled allergen; the effects of lower doses have not been reported. This study assessed the dose-response effects of GSK2190915 10 mg and 50 mg on the early asthmatic response (EAR) to inhaled allergen. METHODS: Nineteen subjects with mild asthma and an EAR were enrolled in a randomized, double-blind, three-way crossover study of GSK2190915 10 mg, 50 mg, and placebo orally once-daily for 3 days. Allergen challenge was performed 2 hours after the third dose. RESULTS: Compared with placebo, GSK2190915 10 mg and 50 mg caused significant, dose-dependent attenuation of the minimum forced expiratory volume at 1 second (FEV1) absolute change from baseline; mean treatment differences were 0.21 L (95% confidence interval [CI] 0.04 L, 0.38 L) and 0.41 L (95% CI 0.24 L, 0.58 L), respectively. GSK2190915 50 mg was more effective than 10 mg; mean difference between treatments was 0.20 L, (95% CI 0.03 L, 0.36 L). Compared with placebo, GSK2190915 50 mg, but not 10 mg, significantly inhibited the weighted mean FEV1 absolute change from baseline. CONCLUSION: GSK2190915 50 mg attenuated the EAR similarly to GSK2190915 100 mg in our previous study, suggesting 50 mg is at the top of the dose-response curve. GSK2190915 10 mg is a suboptimal dose. The EAR can be used to assess the therapeutic dose of a new treatment for asthma.