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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...

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Autores principales: Bifano, Marc, Adamczyk, Robert, Hwang, Carey, Kandoussi, Hamza, Marion, Alan, Bertz, Richard J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2015
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.
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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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