title: Pharmacokinetic interactions between simvastatin and setipiprant, a CRTH2 antagonist.
abstract: OBJECTIVE
  Setipiprant, a selective oral CRTH2 antagonist, has been investigated for the treatment of allergic rhinitis and asthma. In vitro data showed that setipiprant has a weak induction potential on CYP3A4. An interaction at the hepatic level between setipiprant and CYP3A4 substrates was not expected even at the dosing regimen of 1,000 mg setipiprant b.i.d. due to the high plasma protein binding. However, at this dosing regimen, interactions at the gut level could not be excluded.
  
  
  METHODS
  In this single-center, open-label study, 40 mg of simvastatin was administered orally on Day 1, and then concomitantly with setipiprant on Day 10 following 9 days of setipiprant 1,000 mg b.i.d. to 22 healthy male subjects.
  
  
  RESULTS
  In the presence of setipiprant, the simvastatin concentration-time profile was similar to that of simvastatin alone. The concentrations of simvastatin were, however, slightly lower, resulting in a 9 % decrease in C max (geometric mean ratio (GMR) 0.91, 90 % confidence interval (CI) (0.73, 1.13)) and in a 16 % lower AUC0-∞ (GMR 0.84, 90 % CI (0.72, 0.99)). Exposure to simvastatin acid was similar when comparing simvastatin with or without setipiprant. The GMR and 90 % CI for AUC0-∞ were within the 0.8 to 1.25 limits, whereas those for C max were outside (GMR 2.73, 90 % CI (2.11, 3.53)). Moreover, the median t max of simvastatin acid occurred earlier (1.8 h) when combined compared to 3.0 h when administered alone.
  
  
  CONCLUSIONS
  As setipiprant has little impact on simvastatin pharmacokinetics, it does not modulate CYP3A4 in a clinically relevant manner.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland, martine.gehin-beurne@actelion.com.
authors.forename: Martine
authors.initials: M
authors.lastname: Gehin
authors.forename: Patricia N
authors.initials: PN
authors.lastname: Sidharta
authors.forename: Carmela
authors.initials: C
authors.lastname: Gnerre
authors.forename: Alexander
authors.initials: A
authors.lastname: Treiber
authors.forename: Atef
authors.initials: A
authors.lastname: Halabi
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004347:Drug Interactions; D006801:Humans; D007211:Indoles / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008875:Middle Aged; D009281:Naphthalenes / Q000097:blood / Q000493:pharmacokinetics*; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D011982:Receptors, Prostaglandin / Q000037:antagonists & inhibitors; D019821:Simvastatin / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics*; 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; D007211:Indoles; D009281:Naphthalenes; D011971:Receptors, Immunologic; D011982:Receptors, Prostaglandin; C063287:simvastatin acid; D019821:Simvastatin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C036293:prostaglandin D2 receptor