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Effect of a Modified Saquinavir/Ritonavir Dosing Regimen with Lower Dose Lead-In Phase on QTc Interval, Pharmacokinetics, Antiviral Activity and Safety in Treatment-Naïve HIV-1-Infected Patients
BACKGROUND: Saquinavir/ritonavir (1000/100 mg twice daily [BID]) is associated with dose- and exposure-dependent prolongation of the QT interval. The QT risk is considered higher during the first week of therapy, when saquinavir peak exposure has been observed. A modified regimen with a lower dose l...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer International Publishing
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359187/ https://www.ncbi.nlm.nih.gov/pubmed/25742730 http://dx.doi.org/10.1007/s40268-015-0087-7 |
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author | Boffito, Marta Jackson, Akil Pozniak, Anton Giraudon, Mylene Kulkarni, Rohit Abelardo, Maria Connie Patel, Indravadan H. Morcos, Peter N. |
author_facet | Boffito, Marta Jackson, Akil Pozniak, Anton Giraudon, Mylene Kulkarni, Rohit Abelardo, Maria Connie Patel, Indravadan H. Morcos, Peter N. |
author_sort | Boffito, Marta |
collection | PubMed |
description | BACKGROUND: Saquinavir/ritonavir (1000/100 mg twice daily [BID]) is associated with dose- and exposure-dependent prolongation of the QT interval. The QT risk is considered higher during the first week of therapy, when saquinavir peak exposure has been observed. A modified regimen with a lower dose lead-in phase may reduce potential saquinavir-/ritonavir-induced QT prolongations. OBJECTIVE: To explore the effect of the modified saquinavir/ritonavir regimen on QT interval, pharmacokinetics, antiviral activity, and safety in treatment-naïve HIV-1-infected patients. METHODS: Twenty-three HIV-1-infected treatment-naïve patients received saquinavir/ritonavir 500/100 mg BID on days 1–7 and 1000/100 mg BID on days 8–14 in combination with two nucleoside reverse transcriptase inhibitors. The primary endpoint was mean maximum change from dense predose baseline in QT values corrected using Fridericia’s formula (∆QTcF(dense)) across study days. Secondary endpoints included maximum change from time-matched baseline in QTcF, antiviral activity, pharmacokinetics, and safety over the 14 days. RESULTS: The mean maximum ∆QTcF(dense) was 3, 1, 7, 12, and 7 ms on days 3, 4, 7, 10, and 14, respectively. Across all study days, 2/21 patients had a maximum ∆QTcF(dense) ≥30 ms (on day 10); the highest mean ∆QTcF(dense) was <10 ms. During week 1, saquinavir exposure was highest on day 3 and lowest on day 7. All patients showed continuous declines in HIV-RNA; none experienced virologic breakthrough/rebound. The modified regimen was generally well tolerated. CONCLUSION: Treatment initiation with the modified saquinavir/ritonavir regimen in treatment-naïve HIV-1-infected patients reduced saquinavir exposure during week 1, potentially mitigating/reducing QT liability while suppressing HIV-RNA during the course of treatment. |
format | Online Article Text |
id | pubmed-4359187 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-43591872015-03-18 Effect of a Modified Saquinavir/Ritonavir Dosing Regimen with Lower Dose Lead-In Phase on QTc Interval, Pharmacokinetics, Antiviral Activity and Safety in Treatment-Naïve HIV-1-Infected Patients Boffito, Marta Jackson, Akil Pozniak, Anton Giraudon, Mylene Kulkarni, Rohit Abelardo, Maria Connie Patel, Indravadan H. Morcos, Peter N. Drugs R D Original Research Article BACKGROUND: Saquinavir/ritonavir (1000/100 mg twice daily [BID]) is associated with dose- and exposure-dependent prolongation of the QT interval. The QT risk is considered higher during the first week of therapy, when saquinavir peak exposure has been observed. A modified regimen with a lower dose lead-in phase may reduce potential saquinavir-/ritonavir-induced QT prolongations. OBJECTIVE: To explore the effect of the modified saquinavir/ritonavir regimen on QT interval, pharmacokinetics, antiviral activity, and safety in treatment-naïve HIV-1-infected patients. METHODS: Twenty-three HIV-1-infected treatment-naïve patients received saquinavir/ritonavir 500/100 mg BID on days 1–7 and 1000/100 mg BID on days 8–14 in combination with two nucleoside reverse transcriptase inhibitors. The primary endpoint was mean maximum change from dense predose baseline in QT values corrected using Fridericia’s formula (∆QTcF(dense)) across study days. Secondary endpoints included maximum change from time-matched baseline in QTcF, antiviral activity, pharmacokinetics, and safety over the 14 days. RESULTS: The mean maximum ∆QTcF(dense) was 3, 1, 7, 12, and 7 ms on days 3, 4, 7, 10, and 14, respectively. Across all study days, 2/21 patients had a maximum ∆QTcF(dense) ≥30 ms (on day 10); the highest mean ∆QTcF(dense) was <10 ms. During week 1, saquinavir exposure was highest on day 3 and lowest on day 7. All patients showed continuous declines in HIV-RNA; none experienced virologic breakthrough/rebound. The modified regimen was generally well tolerated. CONCLUSION: Treatment initiation with the modified saquinavir/ritonavir regimen in treatment-naïve HIV-1-infected patients reduced saquinavir exposure during week 1, potentially mitigating/reducing QT liability while suppressing HIV-RNA during the course of treatment. Springer International Publishing 2015-03-06 2015-03 /pmc/articles/PMC4359187/ /pubmed/25742730 http://dx.doi.org/10.1007/s40268-015-0087-7 Text en © The Author(s) 2015 https://creativecommons.org/licenses/by-nc/4.0/ Open AccessThis article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited. |
spellingShingle | Original Research Article Boffito, Marta Jackson, Akil Pozniak, Anton Giraudon, Mylene Kulkarni, Rohit Abelardo, Maria Connie Patel, Indravadan H. Morcos, Peter N. Effect of a Modified Saquinavir/Ritonavir Dosing Regimen with Lower Dose Lead-In Phase on QTc Interval, Pharmacokinetics, Antiviral Activity and Safety in Treatment-Naïve HIV-1-Infected Patients |
title | Effect of a Modified Saquinavir/Ritonavir Dosing Regimen with Lower Dose Lead-In Phase on QTc Interval, Pharmacokinetics, Antiviral Activity and Safety in Treatment-Naïve HIV-1-Infected Patients |
title_full | Effect of a Modified Saquinavir/Ritonavir Dosing Regimen with Lower Dose Lead-In Phase on QTc Interval, Pharmacokinetics, Antiviral Activity and Safety in Treatment-Naïve HIV-1-Infected Patients |
title_fullStr | Effect of a Modified Saquinavir/Ritonavir Dosing Regimen with Lower Dose Lead-In Phase on QTc Interval, Pharmacokinetics, Antiviral Activity and Safety in Treatment-Naïve HIV-1-Infected Patients |
title_full_unstemmed | Effect of a Modified Saquinavir/Ritonavir Dosing Regimen with Lower Dose Lead-In Phase on QTc Interval, Pharmacokinetics, Antiviral Activity and Safety in Treatment-Naïve HIV-1-Infected Patients |
title_short | Effect of a Modified Saquinavir/Ritonavir Dosing Regimen with Lower Dose Lead-In Phase on QTc Interval, Pharmacokinetics, Antiviral Activity and Safety in Treatment-Naïve HIV-1-Infected Patients |
title_sort | effect of a modified saquinavir/ritonavir dosing regimen with lower dose lead-in phase on qtc interval, pharmacokinetics, antiviral activity and safety in treatment-naïve hiv-1-infected patients |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359187/ https://www.ncbi.nlm.nih.gov/pubmed/25742730 http://dx.doi.org/10.1007/s40268-015-0087-7 |
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