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

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.

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

“…Drug-drug interactions (DDIs) involving cardiovascular therapeutics and their related toxicity continue to represent serious challenges to effective treatment of patients with heart disease [1][2][3][4][5]. In one previous [5] study, DDIs from co-administration of cardiovascular drugs were implicated in ∼50 % of adverse drug reactions in patients receiving therapy.…”

“…DDIs with the transporter occur because many cardiovascular drugs are substrates for and functional inhibitors of the transporter [4,7,13,14]. This is particularly problematic for cardiovascular drugs with relatively low therapeutic indexes such as antiarrhythmic drugs and oral anticoagulants because coadministration with these drugs can lead to elevated drug plasma concentrations and increased toxicity [7].…”

Edoxaban zur Schlaganfallprophylaxe bei Patienten mit nicht-valvulärem Vorhofflimmern und zur Behandlung venöser Thromboembolien: ein interdisziplinäres Positionspapier

“…Bei gleichzeitiger Anwendung mit Amiodaron, Chinidin oder Verapamil ist keine Dosisreduktion erforderlich [31,35].…”

Atrial Fibrillation and Stroke in Elderly Patients

“…67,70 Edoxaban is also a substrate of cytochrome P-450 3A4 (CYP3A4). 71 There is an increased risk of bleeding associated with concurrent use of NOACs with other anticoagulants, antiplatelet agents and nonsteroidal antiinflammatory drugs.…”