A. Vandell, J. Lee, M. Shi, K. Brown, J. R. Walker; Daiichi Sankyo Pharma Development, Edison, NJ

BACKGROUND: The organic anion transporting polypeptide 1B1 (OATP1B1), encoded by SLCO1B1, mediates hepatic uptake of M4 (a minor metabolite of the novel factor Xa inhibitor edoxaban, of similar potency) but not edoxaban. M4 represents <10% of total edoxaban exposure in healthy subjects. The genetic variant, rs4149056 (T521C), reduces OATP1B1 activity and may affect M4 exposure. This study examined the association of SLCO1B1 genotype with edoxaban and M4 pharmacokinetics (PK).
METHODS: Data from 458 healthy subjects from 14 Phase I clinical studies were pooled. After a single 60 mg oral dose of edoxaban, blood samples were collected to determine edoxaban and M4 plasma concentrations and calculate PK parameters. SLCO1B1 T521C was genotyped with a validated Taqman assay. PK parameters were summarized by genotype (T/T and C carriers) and pairwise comparisons performed.
RESULTS: Baseline characteristics were similar across genotypes. SLCO1B1 genotype had no effect on edoxaban PK. For M4, C carriers had ~25% greater peak and total exposure.
CONCLUSION: A common functional variant of SLCO1B1 did not affect the PK of edoxaban while M4 metabolite peak and total exposure were increased by ~25% in T521C carriers. This increase is unlikely to be clinically significant, due to the small contribution of M4 to overall edoxaban exposure.
Statistical Comparison of Pharmacokinetic Parameters of Edoxaban or M4 by SLCO1B1 genotype
Geometric Mean (CV%)
PK ParameterT/T
N = 384

N= 74
of Geometric

LS Means, % (90% CI)
EdoxabanAUCinf (ng*h/mL)1769 (25.4)1776 (21.3)100.97 (95.89, 106.32)
Cmax (ng/mL)235.5 (43.9)249.8 (41.6)105.35 (96.47, 115.06)
C24 (ng/mL)11.25 (44.0)10.56 (48.5)95.25 (87.51, 103.68)
M4AUCinf (ng*h/mL)139.1 (40.7)178.9 (38.2)126.86 (117.40, 137.08)
Cmax (ng/mL)18.68 (55.0)23.67 (52.5)124.05 (111.90, 137.53)
C24 (ng/mL)0.959 (53.4)1.105 (63.5)114.94 (104.02, 127.00)