Population pharmacokinetics of edoxaban and its main metabolite in a dedicated renal impairment study

J Clin Pharmacol. 2015 Nov;55(11):1268-79. doi: 10.1002/jcph.541. Epub 2015 Jun 30.


A model characterizing the population pharmacokinetics (PK) of edoxaban and its major metabolite, M4, following a single oral dose of 15 mg administered to subjects with varying kidney function was developed. Thirty-two subjects contributed with edoxaban plasma, edoxaban urine, and M4 plasma concentrations. Edoxaban urine concentrations allowed estimation of renal clearance, and high contribution of renal to total clearance enabled estimation of absolute oral bioavailability. A 2-compartment model with delayed absorption and elimination parameterized as renal clearance linearly related to creatinine clearance (CLcr ) and nonrenal clearance forming M4 described edoxaban PK. The PK of M4 was described with a 1-compartment model. For a typical subject (70 kg; CLcr , 100 mL/min) bioavailability, clearance, and central and peripheral volume of distribution for edoxaban was estimated to 72.3%, 21.0 L/h, 95.4 L, and 54.3 L, respectively. For both edoxaban and M4, the model predicted systemic exposure to increase 57.0%, 35.0%, and 11.6% in a subject having CLcr of 30, 50, and 80 mL/min, respectively, compared with a subject having a CLcr of 100 mL/min. Concentration ratios (M4 over edoxaban) were predicted to vary with time after dose, but with minor influence of kidney function and body weight. Results were in agreement with previous analyses.

Keywords: NONMEM; edoxaban; metabolite; pharmacokinetic; renal impairment.

Publication types

  • Controlled Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Dose-Response Relationship, Drug
  • Factor Xa Inhibitors / blood
  • Factor Xa Inhibitors / pharmacokinetics*
  • Factor Xa Inhibitors / urine
  • Female
  • Humans
  • Male
  • Middle Aged
  • Models, Biological*
  • Pyridines / blood
  • Pyridines / pharmacokinetics*
  • Pyridines / urine
  • Renal Insufficiency / metabolism*
  • Thiazoles / blood
  • Thiazoles / pharmacokinetics*
  • Thiazoles / urine


  • Factor Xa Inhibitors
  • Pyridines
  • Thiazoles
  • edoxaban