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

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 sub...

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Main Authors:	Hoch, Matthias, Darpo, Borje, Remenova, Tatiana, Stoltz, Randall, Zhou, Meijian, Kaufmann, Priska, Bruderer, Shirin, Dingemanse, Jasper
Format:	Online
Language:	English
Published:	Dove Medical Press 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277127/

id	pubmed-4277127
recordtype	oai_dc
spelling	pubmed-42771272014-12-31 A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist Hoch, Matthias Darpo, Borje Remenova, Tatiana Stoltz, Randall Zhou, Meijian Kaufmann, Priska Bruderer, Shirin Dingemanse, Jasper Original Research 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. Dove Medical Press 2014-12-17 /pmc/articles/PMC4277127/ /pubmed/25552906 http://dx.doi.org/10.2147/DDDT.S75565 Text en © 2015 Hoch et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Hoch, Matthias Darpo, Borje Remenova, Tatiana Stoltz, Randall Zhou, Meijian Kaufmann, Priska Bruderer, Shirin Dingemanse, Jasper
spellingShingle	Hoch, Matthias Darpo, Borje Remenova, Tatiana Stoltz, Randall Zhou, Meijian Kaufmann, Priska Bruderer, Shirin Dingemanse, Jasper A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist
author_facet	Hoch, Matthias Darpo, Borje Remenova, Tatiana Stoltz, Randall Zhou, Meijian Kaufmann, Priska Bruderer, Shirin Dingemanse, Jasper
author_sort	Hoch, Matthias
title	A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist
title_short	A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist
title_full	A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist
title_fullStr	A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist
title_full_unstemmed	A thorough QT study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist
title_sort	thorough qt study in the context of an uptitration regimen with selexipag, a selective oral prostacyclin receptor agonist
description	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.
publisher	Dove Medical Press
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4277127/
_version_	1613170841761087488

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

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