Drug Design, Development and Therapy (Dec 2014)

A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist

  • Hoch M,
  • Darpo B,
  • Remenova T,
  • Stoltz R,
  • Zhou M,
  • Kaufmann P,
  • Bruderer S,
  • Dingemanse J

Journal volume & issue
Vol. 2015, no. default
pp. 175 – 185

Abstract

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Matthias Hoch,1 Borje Darpo,2,3 Tatiana Remenova,4 Randall Stoltz,5 Meijian Zhou,2 Priska Kaufmann,1 Shirin Bruderer,1 Jasper Dingemanse1 1Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; 2iCardiac Technologies Inc, Rochester, New York, NY, USA; 3Karolinska Institute, Department of Clinical Sciences, Danderyd’s Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden; 4Drug Safety Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland; 5Covance Clinical Research Unit, Evansville, IN, USA Abstract: The effects of selexipag and its active metabolite ACT-333679 on cardiac repolarization were assessed in a thorough QT study as per International Conference on ­Harmonisation E14 guidance. In this randomized, double-blind, placebo/positive-controlled, parallel-group study, healthy male and female subjects were randomized to receive escalating doses of selexipag (n=91) or placebo/moxifloxacin (n=68). Ascending multiple doses of selexipag in the range of 400-1,600 µg or placebo were administered twice daily for 21 days. Following a nested crossover design, subjects in the moxifloxacin/placebo treatment group received a single oral 400 mg dose of moxifloxacin on day 2 or 24. The primary endpoint (QT interval correction using individualized formula [QTcI]) was chosen based on a prospectively defined test applied to on-treatment data. The mean baseline-adjusted placebo-corrected ΔQTcI (ΔΔQTcI) for selexipag was small at all time points and never exceeded 1.4 msec (upper bound of 90% confidence interval [CI], 3.9 msec) on 800 µg or –0.7 msec (upper bound of 90% CI, 2.1 msec) on 1,600 µg. The mean ΔΔQTcI peak effect for moxifloxacin was 7.5 msec (lower bound of 90% CI, 4.8 msec). The exposure-response analysis did not demonstrate a relevant relationship between plasma concentrations of selexipag or ACT-333679 and ΔΔQTcI but, in contrast, a positive slope within the expected range for moxifloxacin. In conclusion, selexipag does not have an effect on cardiac repolarization. Keywords: prostacyclin, corrected QT, TQT, selexipag, moxifloxacin