Population Pharmacokinetics and Dose–Exposure Proportionality of Edoxaban in Healthy Volunteers

Background and Objectives Edoxaban is a novel direct inhibitor of activated factor Xa. A previous human pharmacokinetic study suggested a less than proportional increase in edoxaban exposure at higher dose concentrations, but the quantitative relationship, including the point of inflection, has not yet been fully characterized. The objectives of this analysis were to characterize the population pharmacokinetics and quantify the dose–exposure relationship of edoxaban over a dose range of 10–180 mg. Methods Concentration data from 278 subjects in five phase I clinical studies were used to perform a population pharmacokinetic analysis using non-linear mixed-effects modeling. Model performance was assessed by standard goodness-of-fit diagnostic plots, visual predictive check, and bootstrapping procedures. Results Edoxaban pharmacokinetics were described by a two-compartment model, with first-order absorption preceded by a lag time for absorption ( t lag ). Edoxaban relative bioavailability ( F 1 ) was estimated as 67.2 % and remained constant at the dose range of 10–30 mg. For doses above 30 mg, every 30-mg dose increase was associated with an approximately 6.7 % decrease in F 1 . Sex was identified as a significant covariate on clearance (CL), with female subjects showing 13.1 % lower CL than male subjects. Food was found to affect t lag , but not F 1 . When compared with the fasted state, administration of edoxaban with food prolonged t lag from 0.233 to 0.375 h. Conclusions The population pharmacokinetic model provided an adequate description of the observed data. The analysis results suggested a less than proportional dose–exposure relationship for edoxaban at a dose above 30 mg. A statistically significant sex effect on CL and food effect on t lag were identified but are unlikely to be clinically important.