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Setipiprant, a selective CRTH 2 antagonist, reduces allergen‐induced airway responses in allergic asthmatics
Author(s) -
Diamant Z.,
Sidharta P. N.,
Singh D.,
O'Connor B. J.,
Zuiker R.,
Leaker B. R.,
Silkey M.,
Dingemanse J.
Publication year - 2014
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.12357
Subject(s) - medicine , allergen , placebo , exhaled nitric oxide , methacholine , airway , asthma , immunology , allergy , pharmacology , crossover study , tolerability , antagonist , anesthesia , adverse effect , spirometry , respiratory disease , lung , receptor , pathology , alternative medicine
Summary Background CRTH 2 is a G‐protein‐coupled receptor on T helper2 cells that mediates pro‐inflammatory effects of prostaglandin D 2 in allergic responses. Objective To investigate the tolerability and pharmacokinetics of setipiprant ( ACT ‐129968), a selective orally active CRTH 2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen‐induced airway responses. Methods In this 3‐centre, double‐blinded, placebo‐controlled, cross‐over study, 18 allergic asthmatic males were randomized to setipiprant 1000 mg or matching placebo b.i.d . for 5 consecutive days. Study periods were separated by a washout of ≥ 3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV 1 until 10 h post‐allergen. Airway responsiveness to methacholine and exhaled nitric oxide (e NO ) were measured pre‐ and post‐dosing. The effects of both treatments on the allergen‐induced airway responses were compared by a paired Student's t‐ test. Results Fifteen subjects completed the study per‐protocol and were included in the analysis. Overall, setipiprant was well tolerated and no clinically relevant adverse events occurred. Trough plasma concentrations showed a high inter‐subject variability. Compared with placebo, setipiprant significantly reduced the allergen‐induced late asthmatic response (LAR), inhibiting the area under the response vs. time curve ( AUC (3–10 h) ) by on average 25.6% ( P = 0.006) and significantly protected against the allergen‐induced airway hyperresponsiveness ( AHR ) to methacholine ( P = 0.0029). There was no difference in the early asthmatic response ( EAR ) or in allergen‐induced changes in e NO between treatments. Conclusion and Clinical Relevance Setipiprant at multiple oral doses was well tolerated and reduced both the allergen‐induced LAR and the associated AHR in allergic asthmatics. Our findings confirm that CRTH 2 may be a promising target for the treatment of allergic disorders.