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Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects

A randomized, partial‐blind, repeat‐dose, 3‐period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days...

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Autores principales: Lou, Yu, Buchanan, Ann M., Chen, Shuguang, Ford, Susan L., Gould, Elizabeth, Margolis, David, Spreen, William R., Patel, Parul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132079/
https://www.ncbi.nlm.nih.gov/pubmed/27162089
http://dx.doi.org/10.1002/cpdd.272
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author Lou, Yu
Buchanan, Ann M.
Chen, Shuguang
Ford, Susan L.
Gould, Elizabeth
Margolis, David
Spreen, William R.
Patel, Parul
author_facet Lou, Yu
Buchanan, Ann M.
Chen, Shuguang
Ford, Susan L.
Gould, Elizabeth
Margolis, David
Spreen, William R.
Patel, Parul
author_sort Lou, Yu
collection PubMed
description A randomized, partial‐blind, repeat‐dose, 3‐period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open‐label 400‐mg dose of the positive control moxifloxacin, with a 21‐day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2. QT interval data were obtained by continuous Holter monitoring for approximately 24 hours at baseline (day ‐1) and from 2 hours before to 24 hours after the third dose on day 2. Plasma cabotegravir exposure was approximately 3‐fold above clinically relevant doses. After 3 doses of 150 mg of cabotegravir administered every 12 hours, all upper limits of 2‐sided 90% confidence intervals for ΔΔQTcF (difference in time‐matched change from baseline for QTcF between cabotegravir and placebo) were <10 milliseconds. There was no relationship between cabotegravir plasma concentrations and ΔΔQTcF. No subject receiving cabotegravir had a QTcF value > 450 milliseconds. There were no serious or grade 3 or 4 adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiogram results. These data demonstrate that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization.
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spelling pubmed-51320792016-12-02 Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects Lou, Yu Buchanan, Ann M. Chen, Shuguang Ford, Susan L. Gould, Elizabeth Margolis, David Spreen, William R. Patel, Parul Clin Pharmacol Drug Dev Articles A randomized, partial‐blind, repeat‐dose, 3‐period crossover study (NCT02027454) assessed the effect of cabotegravir on QT interval in healthy subjects. To achieve a supratherapeutic dose, each subject received cabotegravir 150 mg (30 mg × 5 tablets) every 12 hours for a total of 3 doses over 2 days, matching placebo (every 12 hours) over 2 days, or a single open‐label 400‐mg dose of the positive control moxifloxacin, with a 21‐day washout between treatments. Blood samples for pharmacokinetic analyses were collected up to 24 hours after the third dose on day 2. QT interval data were obtained by continuous Holter monitoring for approximately 24 hours at baseline (day ‐1) and from 2 hours before to 24 hours after the third dose on day 2. Plasma cabotegravir exposure was approximately 3‐fold above clinically relevant doses. After 3 doses of 150 mg of cabotegravir administered every 12 hours, all upper limits of 2‐sided 90% confidence intervals for ΔΔQTcF (difference in time‐matched change from baseline for QTcF between cabotegravir and placebo) were <10 milliseconds. There was no relationship between cabotegravir plasma concentrations and ΔΔQTcF. No subject receiving cabotegravir had a QTcF value > 450 milliseconds. There were no serious or grade 3 or 4 adverse events or clinically significant changes in laboratory values, vital signs, or electrocardiogram results. These data demonstrate that cabotegravir at a supratherapeutic dose had no effect on cardiac repolarization. John Wiley and Sons Inc. 2016-06-22 2016 /pmc/articles/PMC5132079/ /pubmed/27162089 http://dx.doi.org/10.1002/cpdd.272 Text en © 2016, The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs (http://creativecommons.org/licenses/by-nc-nd/4.0/) License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
spellingShingle Articles
Lou, Yu
Buchanan, Ann M.
Chen, Shuguang
Ford, Susan L.
Gould, Elizabeth
Margolis, David
Spreen, William R.
Patel, Parul
Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects
title Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects
title_full Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects
title_fullStr Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects
title_full_unstemmed Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects
title_short Effect of Cabotegravir on Cardiac Repolarization in Healthy Subjects
title_sort effect of cabotegravir on cardiac repolarization in healthy subjects
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132079/
https://www.ncbi.nlm.nih.gov/pubmed/27162089
http://dx.doi.org/10.1002/cpdd.272
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