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Drug–Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir

Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transpo...

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Autores principales: Ouwerkerk-Mahadevan, Sivi, Snoeys, Jan, Peeters, Monika, Beumont-Mauviel, Maria, Simion, Alexandru
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756048/
https://www.ncbi.nlm.nih.gov/pubmed/26353895
http://dx.doi.org/10.1007/s40262-015-0314-y
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author Ouwerkerk-Mahadevan, Sivi
Snoeys, Jan
Peeters, Monika
Beumont-Mauviel, Maria
Simion, Alexandru
author_facet Ouwerkerk-Mahadevan, Sivi
Snoeys, Jan
Peeters, Monika
Beumont-Mauviel, Maria
Simion, Alexandru
author_sort Ouwerkerk-Mahadevan, Sivi
collection PubMed
description Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug–drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of simeprevir, respectively, and should be avoided. Clinical studies have shown that simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring.
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spelling pubmed-47560482016-02-26 Drug–Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir Ouwerkerk-Mahadevan, Sivi Snoeys, Jan Peeters, Monika Beumont-Mauviel, Maria Simion, Alexandru Clin Pharmacokinet Review Article Simeprevir is an NS3/4A protease inhibitor approved for the treatment of hepatitis C infection, as a component of combination therapy. Simeprevir is metabolized by the cytochrome P450 (CYP) system, primarily CYP3A, and is a substrate for several drug transporters, including the organic anion transporting polypeptides (OATPs). It is susceptible to metabolic drug–drug interactions with drugs that are moderate or strong CYP3A inhibitors (e.g. ritonavir and erythromycin) or CYP3A inducers (e.g. rifampin and efavirenz); coadministration of these drugs may increase or decrease plasma concentrations of simeprevir, respectively, and should be avoided. Clinical studies have shown that simeprevir is a mild inhibitor of CYP1A2 and intestinal CYP3A but does not inhibit hepatic CYP3A. The effects of simeprevir on these enzymes are of clinical relevance only for narrow-therapeutic-index drugs that are metabolized solely by these enzymes (e.g. oral midazolam). Simeprevir does not have a clinically relevant effect on the pharmacokinetics of rilpivirine, tacrolimus, oral contraceptives and several other drugs metabolized by CYP enzymes. Simeprevir is a substrate and inhibitor of the transporters P-glycoprotein (P-gp), breast cancer resistance protein (BCRP) and OATP1B1/3. Cyclosporine is an inhibitor of OATP1B1/3, BCRP and P-gp, and a mild inhibitor of CYP3A; cyclosporine causes a significant increase in simeprevir plasma concentrations, and coadministration is not recommended. Clinical studies have demonstrated increases in coadministered drug concentrations for drugs that are substrates of the OATP1B1/3, BRCP (e.g. rosuvastatin) and P-gp (e.g. digoxin) transporters; these drugs should be administered with dose titration and or/close monitoring. Springer International Publishing 2015-09-09 2016 /pmc/articles/PMC4756048/ /pubmed/26353895 http://dx.doi.org/10.1007/s40262-015-0314-y 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 Review Article
Ouwerkerk-Mahadevan, Sivi
Snoeys, Jan
Peeters, Monika
Beumont-Mauviel, Maria
Simion, Alexandru
Drug–Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir
title Drug–Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir
title_full Drug–Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir
title_fullStr Drug–Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir
title_full_unstemmed Drug–Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir
title_short Drug–Drug Interactions with the NS3/4A Protease Inhibitor Simeprevir
title_sort drug–drug interactions with the ns3/4a protease inhibitor simeprevir
topic Review Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756048/
https://www.ncbi.nlm.nih.gov/pubmed/26353895
http://dx.doi.org/10.1007/s40262-015-0314-y
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