title: Bioequivalence of different dose-strength tablets of selexipag, a selective prostacyclin receptor agonist, in a multiple-dose up-titration study.
abstract: OBJECTIVE
  Selexipag is a novel, oral, selective prostacyclin (PGI2) receptor agonist in clinical development for the treatment of pulmonary arterial hypertension. Film-coated tablets with strength between 200 and 1,600 μg were used. Bioequivalence between 8 x 200 μg and a new 1,600 μg tablet was evaluated at steady state in healthy male subjects.
  
  
  METHODS
  This was an open-label, 2-treatment, 2-period, crossover, up-titration, phase 1 study. The treatments were selexipag at 1,600 μg b.i.d. for 4.5 days either as 8 x 200 μg tablets (reference: A) or 1 x 1,600 μg tablet (test: B), both preceded by an up-titration phase starting from 400 μg b.i.d. doses, in 200-μg steps every 4th day. Subjects were randomized 1 : 1 to the A-B or B-A sequence. The pharmacokinetics and tolerability of selexipag and its active metabolite, ACT-333679, were investigated.
  
  
  RESULTS
  80 subjects were enrolled in the study: 65 subjects completed the study according to protocol, and 15 subjects withdrew from the study. The most frequent adverse events (AEs) were headache (86%), myalgia (73%), and jaw pain (73%). There was no difference in nature and overall frequency of AEs between the two treatments. Steady state was attained within 3 days of the selexipag 1,600 Î¼g b.i.d.
  
  
  METHODS
  The 90% confidence intervals (CIs) of the geometric mean ratio (B/A) at steady state for AUCÏ and Cmax,ss were within (0.80, 1.25) bioequivalence interval: (0.92, 1.06) and (0.95, 1.14), respectively, for selexipag and (0.95, 1.06) and (0.94, 1.07), respectively, for the active metabolite, ACT-333679.
  
  
  CONCLUSIONS
  Bioequivalence was demonstrated between 8 x 200 μg and 1 x 1,600 μg selexipag at steady state.
authors.forename: Daniela
authors.initials: D
authors.lastname: Baldoni
authors.forename: Shirin
authors.initials: S
authors.lastname: Bruderer
authors.forename: Naguib
authors.initials: N
authors.lastname: Muhsen
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D000328:Adult; D018592:Cross-Over Studies; D006801:Humans; D008297:Male; D011446:Prospective Studies; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D044006:Receptors, Epoprostenol / Q000819:agonists*; D013607:Tablets; D013810:Therapeutic Equivalency
chemical_list: D000081:Acetamides; D011719:Pyrazines; D044006:Receptors, Epoprostenol; D013607:Tablets; C523468:selexipag