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Drug-Drug Interaction Studies of Cardiovascular Drugs Involving P-Glycoprotein, an Efflux Transporter, on the Pharmacokinetics of Edoxaban, an Oral Factor Xa Inhibitor

BACKGROUND: Edoxaban, an oral direct factor Xa inhibitor, is in development for thromboprophylaxis, including prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). P-glycoprotein (P-gp), an efflux transporter, modulates absorption and excretion of xenobiotics. Edoxaba...

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Autores principales: Mendell, Jeanne, Zahir, Hamim, Matsushima, Nobuko, Noveck, Robert, Lee, Frank, Chen, Shuquan, Zhang, George, Shi, Minggao
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781304/
https://www.ncbi.nlm.nih.gov/pubmed/23784266
http://dx.doi.org/10.1007/s40256-013-0029-0
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author Mendell, Jeanne
Zahir, Hamim
Matsushima, Nobuko
Noveck, Robert
Lee, Frank
Chen, Shuquan
Zhang, George
Shi, Minggao
author_facet Mendell, Jeanne
Zahir, Hamim
Matsushima, Nobuko
Noveck, Robert
Lee, Frank
Chen, Shuquan
Zhang, George
Shi, Minggao
author_sort Mendell, Jeanne
collection PubMed
description BACKGROUND: Edoxaban, an oral direct factor Xa inhibitor, is in development for thromboprophylaxis, including prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). P-glycoprotein (P-gp), an efflux transporter, modulates absorption and excretion of xenobiotics. Edoxaban is a P-gp substrate, and several cardiovascular (CV) drugs have the potential to inhibit P-gp and increase drug exposure. OBJECTIVE: To assess the potential pharmacokinetic interactions of edoxaban and 6 cardiovascular drugs used in the management of AF and known P-gp substrates/inhibitors. METHODS: Drug-drug interaction studies with edoxaban and CV drugs with known P-gp substrate/inhibitor potential were conducted in healthy subjects. In 4 crossover, 2-period, 2-treatment studies, subjects received edoxaban 60 mg alone and coadministered with quinidine 300 mg (n = 42), verapamil 240 mg (n = 34), atorvastatin 80 mg (n = 32), or dronedarone 400 mg (n = 34). Additionally, edoxaban 60 mg alone and coadministered with amiodarone 400 mg (n = 30) or digoxin 0.25 mg (n = 48) was evaluated in a single-sequence study and 2-cohort study, respectively. RESULTS: Edoxaban exposure measured as area under the curve increased for concomitant administration of edoxaban with quinidine (76.7 %), verapamil (52.7 %), amiodarone (39.8 %), and dronedarone (84.5 %), and exposure measured as 24-h concentrations for quinidine (11.8 %), verapamil (29.1 %), and dronedarone (157.6 %) also increased. Administration of edoxaban with amiodarone decreased the 24-h concentration for edoxaban by 25.7 %. Concomitant administration with digoxin or atorvastatin had minimal effects on edoxaban exposure. CONCLUSION: Coadministration of the P-gp inhibitors quinidine, verapamil, and dronedarone increased edoxaban exposure. Modest/minimal effects were observed for amiodarone, atorvastatin, and digoxin.
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spelling pubmed-37813042013-09-25 Drug-Drug Interaction Studies of Cardiovascular Drugs Involving P-Glycoprotein, an Efflux Transporter, on the Pharmacokinetics of Edoxaban, an Oral Factor Xa Inhibitor Mendell, Jeanne Zahir, Hamim Matsushima, Nobuko Noveck, Robert Lee, Frank Chen, Shuquan Zhang, George Shi, Minggao Am J Cardiovasc Drugs Original Research Article BACKGROUND: Edoxaban, an oral direct factor Xa inhibitor, is in development for thromboprophylaxis, including prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). P-glycoprotein (P-gp), an efflux transporter, modulates absorption and excretion of xenobiotics. Edoxaban is a P-gp substrate, and several cardiovascular (CV) drugs have the potential to inhibit P-gp and increase drug exposure. OBJECTIVE: To assess the potential pharmacokinetic interactions of edoxaban and 6 cardiovascular drugs used in the management of AF and known P-gp substrates/inhibitors. METHODS: Drug-drug interaction studies with edoxaban and CV drugs with known P-gp substrate/inhibitor potential were conducted in healthy subjects. In 4 crossover, 2-period, 2-treatment studies, subjects received edoxaban 60 mg alone and coadministered with quinidine 300 mg (n = 42), verapamil 240 mg (n = 34), atorvastatin 80 mg (n = 32), or dronedarone 400 mg (n = 34). Additionally, edoxaban 60 mg alone and coadministered with amiodarone 400 mg (n = 30) or digoxin 0.25 mg (n = 48) was evaluated in a single-sequence study and 2-cohort study, respectively. RESULTS: Edoxaban exposure measured as area under the curve increased for concomitant administration of edoxaban with quinidine (76.7 %), verapamil (52.7 %), amiodarone (39.8 %), and dronedarone (84.5 %), and exposure measured as 24-h concentrations for quinidine (11.8 %), verapamil (29.1 %), and dronedarone (157.6 %) also increased. Administration of edoxaban with amiodarone decreased the 24-h concentration for edoxaban by 25.7 %. Concomitant administration with digoxin or atorvastatin had minimal effects on edoxaban exposure. CONCLUSION: Coadministration of the P-gp inhibitors quinidine, verapamil, and dronedarone increased edoxaban exposure. Modest/minimal effects were observed for amiodarone, atorvastatin, and digoxin. Springer International Publishing 2013-06-20 2013 /pmc/articles/PMC3781304/ /pubmed/23784266 http://dx.doi.org/10.1007/s40256-013-0029-0 Text en © The Author(s) 2013 https://creativecommons.org/licenses/by-nc/2.5/ 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
Mendell, Jeanne
Zahir, Hamim
Matsushima, Nobuko
Noveck, Robert
Lee, Frank
Chen, Shuquan
Zhang, George
Shi, Minggao
Drug-Drug Interaction Studies of Cardiovascular Drugs Involving P-Glycoprotein, an Efflux Transporter, on the Pharmacokinetics of Edoxaban, an Oral Factor Xa Inhibitor
title Drug-Drug Interaction Studies of Cardiovascular Drugs Involving P-Glycoprotein, an Efflux Transporter, on the Pharmacokinetics of Edoxaban, an Oral Factor Xa Inhibitor
title_full Drug-Drug Interaction Studies of Cardiovascular Drugs Involving P-Glycoprotein, an Efflux Transporter, on the Pharmacokinetics of Edoxaban, an Oral Factor Xa Inhibitor
title_fullStr Drug-Drug Interaction Studies of Cardiovascular Drugs Involving P-Glycoprotein, an Efflux Transporter, on the Pharmacokinetics of Edoxaban, an Oral Factor Xa Inhibitor
title_full_unstemmed Drug-Drug Interaction Studies of Cardiovascular Drugs Involving P-Glycoprotein, an Efflux Transporter, on the Pharmacokinetics of Edoxaban, an Oral Factor Xa Inhibitor
title_short Drug-Drug Interaction Studies of Cardiovascular Drugs Involving P-Glycoprotein, an Efflux Transporter, on the Pharmacokinetics of Edoxaban, an Oral Factor Xa Inhibitor
title_sort drug-drug interaction studies of cardiovascular drugs involving p-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor xa inhibitor
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781304/
https://www.ncbi.nlm.nih.gov/pubmed/23784266
http://dx.doi.org/10.1007/s40256-013-0029-0
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