Roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor, attenuates allergen-induced asthmatic reactions

Background

Asthma is a chronic inflammatory disease with increasing incidence worldwide. Roflumilast is an oral, once-daily inhibitor of phosphodiesterase type 4 that prevents the breakdown of cyclic adenosine monophosphate levels, leading to inhibition of proinflammatory signaling.

Objective

The objective of this study was to investigate the effects of repeated doses of 250 or 500 μg of roflumilast on asthmatic airway responses to allergen.

Methods

Twenty-three patients with mild asthma with an FEV₁ of 70% of predicted value or greater were enrolled in a randomized, double-blind, placebo-controlled, 3-period crossover study. Patients participated in 3 treatment periods (7-10 days) separated by washout periods (2-5 weeks). Patients received 250 μg of oral roflumilast, 500 μg of roflumilast, or placebo once daily. Allergen challenge was performed at the end of each treatment period, followed by FEV₁ measurements over the ensuing 24 hours.

Results

Late asthmatic reactions (LARs) were reduced by 27% (P=.0110) and 43% (P=.0009) in patients treated with 250 and 500 μg of roflumilast, respectively, versus placebo. Roflumilast, 250 and 500 μg, also attenuated early asthmatic reactions by 25% (P=.0038) and 28% (P=.0046), although not to the same extent as LAR attenuation. Roflumilast was well tolerated. No serious adverse events or discontinuations caused by adverse events were reported.

Conclusion

Once-daily oral roflumilast modestly attenuated early asthmatic reactions and, to a greater extent, LARs to allergen in patients with mild allergic asthma. Pronounced suppression of late responses in an allergen challenge model suggests that roflumilast might have anti-inflammatory activity, which could provide clinical efficacy in chronic inflammatory pulmonary diseases, such as asthma.

Key words: Asthma, roflumilast, phosphodiesterase type 4, allergen provocation, inflammation, late phase

Abbreviations used: AHR, Airway hyperresponsiveness, AUC, Area under the curve, cAMP, Cyclic adenosine monophosphate, COPD, Chronic obstructive pulmonary disease, EAR, Early asthmatic reaction, ICS, Inhaled corticosteroid, LAR, Late asthmatic reaction, PC₂₀FEV₁, Provocative concentration resulting in a 20% decrease in FEV₁, PDE4, Phosphodiesterase type 4