title: Edoxaban drug-drug interactions with ketoconazole, erythromycin, and cyclosporine.
abstract: Edoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P-glycoprotein (P-gp). Three edoxaban drug-drug interaction studies examined the effects of P-gp inhibitors with varying degrees of CYP3A4 inhibition.
  
  
  
  In each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P-gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study.
  
  
  
  Coadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half-life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9-fold and peak exposure by 8.7-fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed.
  
  
  
  Administration of dual inhibitors of P-gp and CYP3A4 increased edoxaban exposure by less than two-fold. This effect appears to be primarily due to inhibition of P-gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects.
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, New Jersey, USA.
authors.forename: Dolly A
authors.initials: DA
authors.lastname: Parasrampuria
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, New Jersey, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mendell
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, New Jersey, USA.
authors.forename: Minggao
authors.initials: M
authors.lastname: Shi
authors.affiliation: Daiichi Sankyo Co., Ltd., Tokyo, Japan.
authors.forename: Nobuko
authors.initials: N
authors.lastname: Matsushima
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, New Jersey, USA.
authors.forename: Hamim
authors.initials: H
authors.lastname: Zahir
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, New Jersey, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Truitt
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D016572:Cyclosporine / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004917:Erythromycin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D013379:Substrate Specificity; D013844:Thiazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; D004917:Erythromycin; D016572:Cyclosporine; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; C552171:edoxaban; D007654:Ketoconazole
keywords: CYP3A4; P-glycoprotein; drug interactions; edoxaban; pharmacokinetics