title: Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers.
abstract: This is a clinical safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) study of a single ascending dose (SAD) and a multiple ascending dose (MAD) of the oral direct factor Xa inhibitor edoxaban in healthy males. The placebo-controlled, single-blind, randomized, 2-part study consists of a SAD arm with 85 subjects (10, 30, 60, 90, 120, 150 mg) and a MAD arm with 36 subjects (90 mg daily, 60 mg twice daily, 120 mg daily). Effects of food and formulation (tablet vs solution) are assessed in a crossover substudy. In the SAD, doses are well tolerated up to 150 mg. Exposure is proportional to dose. PK profiles are consistent across dose with rapid absorption, biphasic elimination, and terminal elimination half-life of 5.8 to 10.7 hours. In the MAD, mean accumulation after daily dosing is 1.10 to 1.13 and consistent with elimination half-life of 8.75 to 10.4 hours. Intrasubject variability ranges from 12% to 17% for area under the curve. In general, plasma edoxaban concentrations are linearly correlated with coagulation parameters. Edoxaban is safe and well tolerated with no dose-dependent increases in adverse events. It is concluded that single and multiple doses of edoxaban are safe and well tolerated up to 150 mg with predictable PK and PD profiles.
authors.affiliation: Daiichi Sankyo Co, Ltd. Tokyo, Japan.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Ogata
authors.forename: Jeanne
authors.initials: J
authors.lastname: Mendell-Harary
authors.forename: Masaya
authors.initials: M
authors.lastname: Tachibana
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Masumoto
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Oguma
authors.forename: Masazumi
authors.initials: M
authors.lastname: Kojima
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kunitada
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001760:Bleeding Time; D004305:Dose-Response Relationship, Drug; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D018565:Food-Drug Interactions; D006207:Half-Life; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D011725:Pyridines / Q000009:adverse effects* / Q000493:pharmacokinetics*; D016037:Single-Blind Method; D013607:Tablets; D013844:Thiazoles / Q000009:adverse effects* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013607:Tablets; D013844:Thiazoles; D015951:Factor Xa; C552171:edoxaban