title: A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist.
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.
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Matthias
authors.initials: M
authors.lastname: Hoch
authors.affiliation: iCardiac Technologies Inc, Rochester, New York, NY, USA ; Karolinska Institute, Department of Clinical Sciences, Danderyd's Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden.
authors.forename: Borje
authors.initials: B
authors.lastname: Darpo
authors.affiliation: Drug Safety Department, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Remenova
authors.affiliation: Covance Clinical Research Unit, Evansville, IN, USA.
authors.forename: Randall
authors.initials: R
authors.lastname: Stoltz
authors.affiliation: iCardiac Technologies Inc, Rochester, New York, NY, USA.
authors.forename: Meijian
authors.initials: M
authors.lastname: Zhou
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Priska
authors.initials: P
authors.lastname: Kaufmann
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Shirin
authors.initials: S
authors.lastname: Bruderer
authors.affiliation: Department of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Jasper
authors.initials: J
authors.lastname: Dingemanse
mesh_terms: D000081:Acetamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D010919:Placebos; D011719:Pyrazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000819:agonists*; D055815:Young Adult
chemical_list: D000081:Acetamides; D024841:Fluoroquinolones; C113936:PTGIR protein, human; D010919:Placebos; D011719:Pyrazines; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; C523468:selexipag; D000077266:Moxifloxacin
keywords: TQT; corrected QT; moxifloxacin; prostacyclin; selexipag