Key result
Coadministration of edoxaban with the P-gp inhibitors dronedarone, quinidine, and verapamil increased edoxaban total exposure by 84.5%, 76.7%, and 52.7% respectively compared to edoxaban alone.
Why the study?
Does coadministration of cardiovascular P-glycoprotein inhibitors alter the pharmacokinetics of edoxaban in healthy subjects?
RCT (n=220)
Open-label
Randomized
Yes
Does coadministration of cardiovascular P-glycoprotein inhibitors alter the pharmacokinetics of edoxaban in healthy subjects?
Coadministration of edoxaban with P-glycoprotein inhibitors such as quinidine, verapamil, and dronedarone significantly increases edoxaban exposure, highlighting the potential need for dose adjustments in clinical practice.
Answers are grounded in this paper and cite their sources.
May warrant edoxaban dose caution with these inhibitors; leaves open outcome trials in patients.
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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Mendell et al. (2013) conducted an RCT in Healthy subjects (n=220). Edoxaban coadministered with P-gp inhibitors (dronedarone, quinidine, verapamil, amiodarone, digoxin, atorvastatin) vs. Edoxaban 60 mg alone was evaluated on Edoxaban AUC0-inf (with dronedarone vs alone) (Ratio 184.5%, 95% CI 177.9-191.4). Coadministration of edoxaban with the P-gp inhibitors dronedarone, quinidine, and verapamil increased edoxaban total exposure by 84.5%, 76.7%, and 52.7% respectively compared to edoxaban alone.
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