title: Population Pharmacokinetics of Edoxaban in Patients with Non-Valvular Atrial Fibrillation in the ENGAGE AF-TIMI 48 Study, a Phase III Clinical Trial.
abstract: Edoxaban is a novel factor Xa inhibitor. This study characterizes the population pharmacokinetics of edoxaban in patients with non-valvular atrial fibrillation (NVAF) included in the phase III ENGAGE AF-TIMI 48 study, evaluates covariates for the dose-exposure relationship in this population, and assesses the impact of protocol-specified dose reductions on exposure using simulations.
  
  
  
  Model development was performed using NONMEM(®) and based on sparse data from the ENGAGE AF-TIMI 48 study augmented with dense data from 13 phase I studies to inform and stabilize the model. The influence of body weight (WT), creatinine clearance (CLCR), concomitant P-glycoprotein (P-gp) inhibitors, age, sex, race, and NVAF on pharmacokinetic parameters was evaluated based on statistical significance and clinical relevance.
  
  
  
  A two-compartment model with first-order elimination and first-order absorption after an absorption lag-time best described the data. Apparent volume and clearance terms increased with increasing WT. Apparent renal clearance increased with increasing CLCR. Apparent non-renal, renal, and inter-compartmental clearance terms differed between phase I volunteers and NVAF patients. Asian patients were found to have increased apparent central volume of distribution, bioavailability, and total apparent clearance. Concomitant P-gp inhibitors increased the bioavailability statistically significantly, but this did not reach clinical relevance.
  
  
  
  Edoxaban disposition and the variability in this disposition, including influence of covariates, after oral administration were adequately characterized in patients with NVAF. The 50 % dose reduction in patients with low WT (≤60 kg), moderate renal impairment (CLCR ≤50 mL/min), or concomitant P-gp inhibitors led to 30 % lower exposure than in the other patients.
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden. e.krekels@lacdr.leidenuniv.nl.|LACDR Division of Pharmacology, PO Box 9502, 2300 RA, Leiden, The Netherlands. e.krekels@lacdr.leidenuniv.nl.
authors.forename: Elke H J
authors.initials: EH
authors.lastname: Krekels
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Ronald
authors.initials: R
authors.lastname: Niebecker
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.affiliation: Daiichi Sankyo Pharma Development, Edison, NJ, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Miller
authors.affiliation: Daiichi Sankyo, Co., Ltd., Tokyo, Japan.
authors.forename: Takako
authors.initials: T
authors.lastname: Shimizu
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Kristin E
authors.initials: KE
authors.lastname: Karlsson
authors.affiliation: Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Christian T
authors.initials: CT
authors.lastname: Ruff
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Ulrika S H
authors.initials: US
authors.lastname: Simonsson
authors.affiliation: Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Siv
authors.initials: S
authors.lastname: Jönsson
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000627:therapeutic use; D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001281:Atrial Fibrillation / Q000188:drug therapy*; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D008954:Models, Biological; D008962:Models, Theoretical; D011725:Pyridines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C552171:edoxaban