Bioequivalence of different dose-strength tablets of selexipag, a selective prostacyclin receptor agonist, in a multiple-dose up-titration study

Objective: Selexipag is a novel, oral, selective prostacyclin (PGI(2)) receptor agonist in clinical development for the treatment of pulmonary arterial hypertension. Film-coated tablets with strength between 200 and 1,600 mu g were used. Bioequivalence between 8 x 200 mu g and a new 1,600 mu g tablet was evaluated at steady state in healthy male subjects. Materials and methods: This was an open-label, 2-treatment, 2-period, crossover, up-titration, phase 1 study. The treatments were selexipag at 1,600 mu g b.i.d. for 4.5 days either as 8 x 200 mu g tablets (reference: A) or 1 x 1,600 mu g tablet (test: B), both preceded by an up-titration phase starting from 400 mu g b.i.d. doses, in 200-mu g 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 gig bid. treatments. The 90% confidence intervals (CIs) of the geometric mean ratio (B/A) at steady state for AUC(tau) and C-max,C-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 jig and 1 x 1,600 jag selexipag at steady state.