The aim of a study was to evaluate the population pharmacokinetics ( PK ) and exposure-response relationship of Edoxaban ( Lixiana, Savaysa ) in patients with non-valvular atrial fibrillation ( AF ).
Concentration data from 1,134 subjects in 11 clinical studies ( eight phase I, one phase II, and two phase III ) were used to perform a population PK analysis, including estimation of the bioavailability and quantification of the effects of P-glycoprotein ( P-gp ) inhibitors as well as renal impairment on Edoxaban pharmacokinetics.
The potential relationship between Edoxaban pharmacokinetics exposure and incidence of bleeding events was explored based on data from 893 atrial fibrillation patients.
Absolute bioavailability of Edoxaban was estimated as 58.3%.
With oral dosing of Edoxaban, co-administration of various P-gp inhibitors significantly increased Edoxaban bioavailability and decreased volume of distribution ( V2 ), resulting in a predicted increase of 33-77% in area under the curve ( AUC ) and 65-104% in Cmax.
A much smaller increase was seen in Edoxaban concentration at 24 h post-dose ( C24, -24 to 38 % ), due to decreased V2 and shortened elimination half-life.
With IV dosing of Edoxaban, co-administration of the P-gp inhibitor Quinidine decreased both Edoxaban clearance ( CL ) and V2, resulting in an increase of 32% in AUC and 66% in C24.
Creatinine clearance was a significant covariate on renal clearance, whereas age and body weight significantly affected non-renal clearance.
Model-predicted steady state Cmin was slightly higher, but AUC was comparable for patients who had severe renal impairment and received Edoxaban 15 mg once daily ( QD ) versus patients who had normal renal function or mild renal impairment and received Edoxaban 30 mg QD.
In conclusion, the model provided reasonable estimation with regard to the absolute bioavailability of Edoxaban, the magnitude of change in Edoxaban exposure upon co-administration of P-gp inhibitors, and the impact of renal impairment on Edoxaban clearance.
Analysis results supported a 50 % dose reduction scheme for subjects with severe renal impairment. ( Xagena )
Yin OQ et al, Eur J Clin Pharmacol 2014;70:1339-1351