title: Population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism--the Hokusai-VTE phase 3 study.
abstract: OBJECTIVE
  This study characterized the population pharmacokinetics of edoxaban in patients with symptomatic deep-vein thrombosis and/or pulmonary embolism in the Hokusai-VTE phase 3 study. The impact of the protocol-specified 50% dose reductions applied to patients with body weight ≤ 60 kg, creatinine clearance (CL(cr)) of 30 to 50 ml min(-1) or concomitant P-glycoprotein inhibitor on edoxaban exposure was assessed using simulations.
  
  
  METHODS
  The sparse data from Hokusai-VTE, 9531 concentrations collected from 3707 patients, were pooled with data from 13 phase 1 studies. In the analysis, the covariate relationships used for dose reductions were estimated and differences between healthy subjects and patients as well as additional covariate effects of age, race and gender were explored based on statistical and clinical significance.
  
  
  RESULTS
  A linear two-compartment model with first order absorption preceded by a lag time best described the data. Allometrically scaled body weight was included on disposition parameters. Apparent clearance was parameterized as non-renal and renal. The latter increased non-linearly with increasing CL(cr). Compared with healthy volunteers, inter-compartmental clearance and the CL(cr) covariate effect were different in patients (+64.6% and +274%). Asian patients had a 22.6% increased apparent central volume of distribution. The effect of co-administration of P-glycoprotein inhibitors seen in phase 1 could not be confirmed in the phase 3 data. Model-based simulations revealed lower exposure in dose-reduced compared with non-dose-reduced patients.
  
  
  CONCLUSIONS
  The adopted dose-reduction strategy resulted in reduced exposure compared with non-dose-reduced, thereby overcompensating for covariate effects. The clinical impact of these differences on safety and efficacy remains to be evaluated.
authors.affiliation: Department of Pharmaceutical Biosciences,, Uppsala University, Uppsala, Sweden and.
authors.forename: Ronald
authors.initials: R
authors.lastname: Niebecker
authors.affiliation: Department of Pharmaceutical Biosciences,, Uppsala University, Uppsala, Sweden and.
authors.forename: Siv
authors.initials: S
authors.lastname: Jönsson
authors.affiliation: Department of Pharmaceutical Biosciences,, Uppsala University, Uppsala, Sweden and.
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
authors.affiliation: Modelling and Simulation, Translational Medicine and Clinical Pharmacology, Daiichi Sankyo Pharma Development, Edison, New Jersey, USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Miller
authors.affiliation: Department of Pharmaceutical Biosciences,, Uppsala University, Uppsala, Sweden and.
authors.forename: Joakim
authors.initials: J
authors.lastname: Nyberg
authors.affiliation: Department of Pharmaceutical Biosciences,, Uppsala University, Uppsala, Sweden and.
authors.forename: Elke H J
authors.initials: EH
authors.lastname: Krekels
authors.affiliation: Department of Pharmaceutical Biosciences,, Uppsala University, Uppsala, Sweden and.
authors.forename: Ulrika S H
authors.initials: US
authors.lastname: Simonsson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D065427:Factor Xa Inhibitors / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011655:Pulmonary Embolism / Q000188:drug therapy*; D011725:Pyridines / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000493:pharmacokinetics*; D020246:Venous Thrombosis / Q000188:drug therapy*
chemical_list: D065427:Factor Xa Inhibitors; D011725:Pyridines; D013844:Thiazoles; C552171:edoxaban
keywords: deep-vein thrombosis; edoxaban; nonmem; population pharmacokinetics; pulmonary embolism