title: Drug-drug interaction studies of cardiovascular drugs involving P-glycoprotein, an efflux transporter, on the pharmacokinetics of edoxaban, an oral factor Xa inhibitor.
abstract: 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.
  
  
  CONCLUSIONS
  Coadministration of the P-gp inhibitors quinidine, verapamil, and dronedarone increased edoxaban exposure. Modest/minimal effects were observed for amiodarone, atorvastatin, and digoxin.
authors.affiliation: Daiichi Sankyo Pharma Development, 399 Thornall Street, Edison, NJ, 08837, USA, jmendell@dsi.com.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mendell
authors.forename: Hamim
authors.initials: H
authors.lastname: Zahir
authors.forename: Nobuko
authors.initials: N
authors.lastname: Matsushima
authors.forename: Robert
authors.initials: R
authors.lastname: Noveck
authors.forename: Frank
authors.initials: F
authors.lastname: Lee
authors.forename: Shuquan
authors.initials: S
authors.lastname: Chen
authors.forename: George
authors.initials: G
authors.lastname: Zhang
authors.forename: Minggao
authors.initials: M
authors.lastname: Shi
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002317:Cardiovascular Agents / Q000494:pharmacology*; D015331:Cohort Studies; D018592:Cross-Over Studies; D004347:Drug Interactions; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D011725:Pyridines / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000925:Anticoagulants; D002317:Cardiovascular Agents; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C552171:edoxaban