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An Open-Label Investigation into Drug–Drug Interactions Between Multiple Doses of Daclatasvir and Single-Dose Cyclosporine or Tacrolimus in Healthy Subjects
BACKGROUND AND OBJECTIVE: Chronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug–drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between...
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/PMC4544506/ https://www.ncbi.nlm.nih.gov/pubmed/25896946 http://dx.doi.org/10.1007/s40261-015-0279-5 |
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author | Bifano, Marc Adamczyk, Robert Hwang, Carey Kandoussi, Hamza Marion, Alan Bertz, Richard J. |
author_facet | Bifano, Marc Adamczyk, Robert Hwang, Carey Kandoussi, Hamza Marion, Alan Bertz, Richard J. |
author_sort | Bifano, Marc |
collection | PubMed |
description | BACKGROUND AND OBJECTIVE: Chronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug–drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between daclatasvir—a pan-genotypic HCV NS5A inhibitor with clinical efficacy in multiple regimens (including all-oral)—and cyclosporine or tacrolimus in healthy subjects. METHODS: Healthy fasted subjects (aged 18–49 years; body mass index 18–32 kg/m(2)) received single oral doses of cyclosporine 400 mg on days 1 and 9, and daclatasvir 60 mg once daily on days 4–11 (group 1, n = 14), or a single oral dose of tacrolimus 5 mg on days 1 and 13, and daclatasvir 60 mg once daily on days 8–19 (group 2, n = 14). Blood samples for pharmacokinetic analysis [by liquid chromatography with tandem mass spectrometry (LC–MS/MS)] were collected on days 1 and 9 for cyclosporine (72 h), on days 1 and 13 for tacrolimus (168 h) and on days 8 and 9 (group 1) or on days 12 and 13 (group 2) for daclatasvir (24 h). Plasma concentrations were determined by validated LC–MS/MS methods. RESULTS: Daclatasvir did not affect the pharmacokinetic parameters of cyclosporine or tacrolimus, and tacrolimus did not affect the pharmacokinetic parameters of daclatasvir. Co-administration of cyclosporine resulted in a 40 % increase in the area under the concentration–time curve of daclatasvir but did not affect its maximum observed concentration. CONCLUSION: On the basis of these observations in healthy subjects, no clinically relevant DDIs between daclatasvir and cyclosporine or tacrolimus are anticipated in liver transplant recipients infected with HCV; dose adjustments during co-administration are unlikely to be required. |
format | Online Article Text |
id | pubmed-4544506 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | Springer International Publishing |
record_format | MEDLINE/PubMed |
spelling | pubmed-45445062015-08-25 An Open-Label Investigation into Drug–Drug Interactions Between Multiple Doses of Daclatasvir and Single-Dose Cyclosporine or Tacrolimus in Healthy Subjects Bifano, Marc Adamczyk, Robert Hwang, Carey Kandoussi, Hamza Marion, Alan Bertz, Richard J. Clin Drug Investig Original Research Article BACKGROUND AND OBJECTIVE: Chronic hepatitis C virus (HCV) infection is a major cause of liver transplantation. Drug–drug interactions (DDIs) with cyclosporine and tacrolimus hindered the use of first-generation protease inhibitors in transplant recipients. The current study investigated DDIs between daclatasvir—a pan-genotypic HCV NS5A inhibitor with clinical efficacy in multiple regimens (including all-oral)—and cyclosporine or tacrolimus in healthy subjects. METHODS: Healthy fasted subjects (aged 18–49 years; body mass index 18–32 kg/m(2)) received single oral doses of cyclosporine 400 mg on days 1 and 9, and daclatasvir 60 mg once daily on days 4–11 (group 1, n = 14), or a single oral dose of tacrolimus 5 mg on days 1 and 13, and daclatasvir 60 mg once daily on days 8–19 (group 2, n = 14). Blood samples for pharmacokinetic analysis [by liquid chromatography with tandem mass spectrometry (LC–MS/MS)] were collected on days 1 and 9 for cyclosporine (72 h), on days 1 and 13 for tacrolimus (168 h) and on days 8 and 9 (group 1) or on days 12 and 13 (group 2) for daclatasvir (24 h). Plasma concentrations were determined by validated LC–MS/MS methods. RESULTS: Daclatasvir did not affect the pharmacokinetic parameters of cyclosporine or tacrolimus, and tacrolimus did not affect the pharmacokinetic parameters of daclatasvir. Co-administration of cyclosporine resulted in a 40 % increase in the area under the concentration–time curve of daclatasvir but did not affect its maximum observed concentration. CONCLUSION: On the basis of these observations in healthy subjects, no clinically relevant DDIs between daclatasvir and cyclosporine or tacrolimus are anticipated in liver transplant recipients infected with HCV; dose adjustments during co-administration are unlikely to be required. Springer International Publishing 2015-04-21 2015 /pmc/articles/PMC4544506/ /pubmed/25896946 http://dx.doi.org/10.1007/s40261-015-0279-5 Text en © The Author(s) 2015 Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. |
spellingShingle | Original Research Article Bifano, Marc Adamczyk, Robert Hwang, Carey Kandoussi, Hamza Marion, Alan Bertz, Richard J. An Open-Label Investigation into Drug–Drug Interactions Between Multiple Doses of Daclatasvir and Single-Dose Cyclosporine or Tacrolimus in Healthy Subjects |
title | An Open-Label Investigation into Drug–Drug Interactions Between Multiple Doses of Daclatasvir and Single-Dose Cyclosporine or Tacrolimus in Healthy Subjects |
title_full | An Open-Label Investigation into Drug–Drug Interactions Between Multiple Doses of Daclatasvir and Single-Dose Cyclosporine or Tacrolimus in Healthy Subjects |
title_fullStr | An Open-Label Investigation into Drug–Drug Interactions Between Multiple Doses of Daclatasvir and Single-Dose Cyclosporine or Tacrolimus in Healthy Subjects |
title_full_unstemmed | An Open-Label Investigation into Drug–Drug Interactions Between Multiple Doses of Daclatasvir and Single-Dose Cyclosporine or Tacrolimus in Healthy Subjects |
title_short | An Open-Label Investigation into Drug–Drug Interactions Between Multiple Doses of Daclatasvir and Single-Dose Cyclosporine or Tacrolimus in Healthy Subjects |
title_sort | open-label investigation into drug–drug interactions between multiple doses of daclatasvir and single-dose cyclosporine or tacrolimus in healthy subjects |
topic | Original Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4544506/ https://www.ncbi.nlm.nih.gov/pubmed/25896946 http://dx.doi.org/10.1007/s40261-015-0279-5 |
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