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The effects of apremilast on the QTc interval in healthy male volunteers: a formal, thorough QT study

Objective: This study was conducted to evaluate the effect of apremilast and its major metabolites on the placebo-corrected change-from-baseline QTc interval of an electrocardiogram (ECG). Materials and methods: Healthy male subjects received each of 4 treatments in a randomized, crossover manner. I...

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Autores principales: Palmisano, Maria, Wu, Anfan, Assaf, Mahmoud, Liu, Liangang, Park, C. Hyung, Savant, Ishani, Liu, Yong, Zhou, Simon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Dustri-Verlag Dr. Karl Feistle 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949396/
https://www.ncbi.nlm.nih.gov/pubmed/27285466
http://dx.doi.org/10.5414/CP202555
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author Palmisano, Maria
Wu, Anfan
Assaf, Mahmoud
Liu, Liangang
Park, C. Hyung
Savant, Ishani
Liu, Yong
Zhou, Simon
author_facet Palmisano, Maria
Wu, Anfan
Assaf, Mahmoud
Liu, Liangang
Park, C. Hyung
Savant, Ishani
Liu, Yong
Zhou, Simon
author_sort Palmisano, Maria
collection PubMed
description Objective: This study was conducted to evaluate the effect of apremilast and its major metabolites on the placebo-corrected change-from-baseline QTc interval of an electrocardiogram (ECG). Materials and methods: Healthy male subjects received each of 4 treatments in a randomized, crossover manner. In the 2 active treatment periods, apremilast 30 mg (therapeutic exposure) or 50 mg (supratherapeutic exposure) was administered twice daily for 9 doses. A placebo control was used to ensure double-blind treatment of apremilast, and an open-label, single dose of moxifloxacin 400 mg was administered as a positive control. ECGs were measured using 24-hour digital Holter monitoring. Results: The two-sided 98% confidence intervals (CIs) for ΔΔQTcI of moxifloxacin completely exceeded 5 ms 2 – 4 hours postdose. For both apremilast dose studies, the least-squares mean ΔΔQTcI was < 1 ms at all time points, and the upper limit of two-sided 90% CIs was < 10 ms. There were no QT/QTc values > 480 ms or a change from baseline > 60 ms. Exploratory evaluation of pharmacokinetic/pharmacodynamic data showed no trend between the changes in QT/QTc interval and the concentration of apremilast or its major metabolites M12 and M14. Conclusions: Apremilast did not prolong the QT interval and appears to be safe and well tolerated up to doses of 50 mg twice daily.
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spelling pubmed-49493962016-08-03 The effects of apremilast on the QTc interval in healthy male volunteers: a formal, thorough QT study Palmisano, Maria Wu, Anfan Assaf, Mahmoud Liu, Liangang Park, C. Hyung Savant, Ishani Liu, Yong Zhou, Simon Int J Clin Pharmacol Ther Research Article Objective: This study was conducted to evaluate the effect of apremilast and its major metabolites on the placebo-corrected change-from-baseline QTc interval of an electrocardiogram (ECG). Materials and methods: Healthy male subjects received each of 4 treatments in a randomized, crossover manner. In the 2 active treatment periods, apremilast 30 mg (therapeutic exposure) or 50 mg (supratherapeutic exposure) was administered twice daily for 9 doses. A placebo control was used to ensure double-blind treatment of apremilast, and an open-label, single dose of moxifloxacin 400 mg was administered as a positive control. ECGs were measured using 24-hour digital Holter monitoring. Results: The two-sided 98% confidence intervals (CIs) for ΔΔQTcI of moxifloxacin completely exceeded 5 ms 2 – 4 hours postdose. For both apremilast dose studies, the least-squares mean ΔΔQTcI was < 1 ms at all time points, and the upper limit of two-sided 90% CIs was < 10 ms. There were no QT/QTc values > 480 ms or a change from baseline > 60 ms. Exploratory evaluation of pharmacokinetic/pharmacodynamic data showed no trend between the changes in QT/QTc interval and the concentration of apremilast or its major metabolites M12 and M14. Conclusions: Apremilast did not prolong the QT interval and appears to be safe and well tolerated up to doses of 50 mg twice daily. Dustri-Verlag Dr. Karl Feistle 2016-08 2016-06-10 /pmc/articles/PMC4949396/ /pubmed/27285466 http://dx.doi.org/10.5414/CP202555 Text en © Dustri-Verlag Dr. K. Feistle http://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Palmisano, Maria
Wu, Anfan
Assaf, Mahmoud
Liu, Liangang
Park, C. Hyung
Savant, Ishani
Liu, Yong
Zhou, Simon
The effects of apremilast on the QTc interval in healthy male volunteers: a formal, thorough QT study
title The effects of apremilast on the QTc interval in healthy male volunteers: a formal, thorough QT study
title_full The effects of apremilast on the QTc interval in healthy male volunteers: a formal, thorough QT study
title_fullStr The effects of apremilast on the QTc interval in healthy male volunteers: a formal, thorough QT study
title_full_unstemmed The effects of apremilast on the QTc interval in healthy male volunteers: a formal, thorough QT study
title_short The effects of apremilast on the QTc interval in healthy male volunteers: a formal, thorough QT study
title_sort effects of apremilast on the qtc interval in healthy male volunteers: a formal, thorough qt study
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4949396/
https://www.ncbi.nlm.nih.gov/pubmed/27285466
http://dx.doi.org/10.5414/CP202555
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