TABLE 6

Pharmacokinetic parameters of apixaban following a single oral dose of apixaban or i.v. dose of [14C]apixaban to male bile duct-cannulated Sprague-Dawley rats

Oral Dose in Intact Rats (4 mg/kg) (n = 3)Intravenous Dose in BDC Rats (2 mg/kg) (n = 3)
WT ControlP-gp-KOBCRP-KOWT GF-120918WT ControlWT GF-120918WT CharcoalP-gp-KOBCRP-KO
AUC0-∞ (µg·h/ml)1.39 ± 0.363.34 ± 0.375.71 ± 1.456.57 ± 1.871.41 ± 0.232.84 ± 0.761.02 ± 0.022.04 ± 0.092.34 ± 0.68
Cmax (µg/ml)0.42 ± 0.080.94 ± 0.111.92 ± 0.772.87 ± 0.802.26 ± 0.251.97 ± 0.321.64 ± 0.272.16 ± 0.292.37 ± 0.11
C10 (C8, i.v.) (ng/ml)a27.8 ± 6.460.9 ± 28.464.1 ± 11.330.6 ± 16.34.5 ± 1.646.1 ± 38.82.8 ± 0.18.6 ± 3.919.5 ± 7.4
T1/2 (h)3.3 ± 1.73.8 ± 0.42.5 ± 0.61.6 ± 0.31.2 ± 0.62.8 ± 0.50.8 ± 0.21.1 ± 0.32.1 ± 1.4
CL/F, CL (l/h/kg)1.5 ± 0.40.6 ± 0.10.4 ± 0.10.3 ± 0.11.4 ± 0.60.7 ± 0.22.0 ± 0.10.8 ± 0.20.9 ± 0.3
Vs/F, Vs (l/kg)5.8 ± 1.12.4 ± 0.71.1 ± 0.20.7 ± 0.20.9 ± 0.11.6 ± 0.31.2 ± 0.20.7 ± 0.11.8 ± 1.2
MRT (h)3.8 ± 0.33.8 ± 1.02.9 ± 0.22.1 ± 0.20.6 ± 0.11.7 ± 0.40.6 ± 0.10.8 ± 0.31.4 ± 0.5
Fb4971122140NANANANANA
Cmax/ C10 (C8, i.v.)1515299350243586274121
CLR (l/h/kg),% totalcNDNDNDND0.71(51%)0.35(50%)0.78(39%)0.39(43%)0.30(33%)
CLIE (l/h/kg),% totalNDNDNDND0.30(21%)0.10(14%)0.55(28%)0.22(24%)0.34(37%)
CL(biliary+met)
(l/h/kg),% totalNDNDNDND0.39(28%)0.25(36%)0.67(33%)0.29%33%)0.26(30%)

  • AUC, area under the plasma concentration versus time curve; BCRP, breast cancer resistance protein; BDC, bile duct cannulation; CL, clearance; F, bioavailability; KO, knockout; MRT, mean residence time; NA, not available; ND, not determined; P-gp, P-glycoprotein; WT, wild-type.

  • ↵a Samples were taken at different time points.

  • ↵b Bioavailability was overestimated because the AUC values of bile duct-cannulated animals were used where enterohepatic recirculation could not be considered. The >100% bioavailability in the BCRP-KO rats and after the treatments with GF-120918 reflected the increased absorption in transporter knockout rats and the increased urinary clearance of apixaban after i.v. administration of BDC rats compared with oral administration of intact rats in addition to elimination of potential low level of enterohepatic recirculation in intact rats, both of which reduced the apparent apixaban AUC after i.v. administration.

  • ↵c The protein binding of apixaban in rat plasma was 96%, therefore, glomerular filtration rate × Fu = 0.31 × 0.04 = 0.012 l/h/kg.