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




Drug-Drug Interaction Studies of Cardiovascular Drugs Involving P-Glycoprotein, an Efflux Transporter, on the Pharmacokinetics of Edoxaban, an Oral Factor Xa Inhibitor - Descarga este documento en PDF. Documentación en PDF para descargar gratis. Disponible también para leer online.

American Journal of Cardiovascular Drugs

, Volume 13, Issue 5, pp 331–342

First Online: 20 June 2013

Abstract

BackgroundEdoxaban, 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.

ObjectiveTo assess the potential pharmacokinetic interactions of edoxaban and 6 cardiovascular drugs used in the management of AF and known P-gp substrates-inhibitors.

MethodsDrug-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.

ResultsEdoxaban 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.

ConclusionCoadministration 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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Autor: Jeanne Mendell - Hamim Zahir - Nobuko Matsushima - Robert Noveck - Frank Lee - Shuquan Chen - George Zhang - Minggao Shi

Fuente: https://link.springer.com/



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