title: Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics.
abstract: BACKGROUND
  CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects of prostaglandin D2 in allergic responses.
  
  
  OBJECTIVE
  To investigate the tolerability and pharmacokinetics of setipiprant (ACT-129968), a selective orally active CRTH2 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 FEV1 until 10 h post-allergen. Airway responsiveness to methacholine and exhaled nitric oxide (eNO) 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 eNO between treatments.
  
  
  CONCLUSIONS
  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 CRTH2 may be a promising target for the treatment of allergic disorders.
authors: Centre for Human Drug Research, Leiden, The Netherlands.
authors: Z
authors: Z
authors: Diamant
authors: P N
authors: PN
authors: Sidharta
authors: D
authors: D
authors: Singh
authors: B J
authors: BJ
authors: O'Connor
authors: R
authors: R
authors: Zuiker
authors: B R
authors: BR
authors: Leaker
authors: M
authors: M
authors: Silkey
authors: J
authors: J
authors: Dingemanse
mesh_terms: D000328:Adult; D000485:Allergens / Q000276:immunology*; D018927:Anti-Asthmatic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology*; D001985:Bronchial Provocation Tests; D045853:Exhalation; D005541:Forced Expiratory Volume / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use*; D009569:Nitric Oxide / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors*; D012129:Respiratory Function Tests; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: C583159:2-(2-(1-naphthoyl)-8-fluoro-3,4-dihydro-1H-pyrido(4,3-b)indol-5(2H)-yl)acetic acid; D000485:Allergens; D018927:Anti-Asthmatic Agents; D007211:Indoles; D009281:Naphthalenes; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; D009569:Nitric Oxide; C036293:prostaglandin D2 receptor
keywords: CRTH2 antagonist; allergen bronchoprovocation test; asthma; setipiprant