Dosing Route | Oral Dose in Intact Dogs (n = 4) (5 mg/kg) | I.V. Dose in BDC Dogs (n = 2) (1 mg/kg) | ||||
---|---|---|---|---|---|---|
AC Treatment | Control | AC (0.25 h) | AC (1 h) | AC (3 h) | Control | AC (in the same dog) |
AUC0-24 (AUC0–∞ i.v.) (reduction) (μg•h/ml) | 78.6 ± 7.0 (NA) | 59.5 ± 4.6 (24%) | 63.9 ± 5.4 (19%) | 49.2 ± 1.8 (37%) | 24.8, 9.30 (NA) | 20.1, 5.60 (19, 39%) |
Cmax (μg/ml) | 9.35 ± 1.33 | 8.42 ± 0.82 | 8.99 ± 0.91 | 8.07 ± 0.80 | 6.97, 4.43 | 6.23, 4.33 |
C8 (C24)a,b (μg/ml) | 5.23 ± 1.02 (0.60 ± 0.28) | 2.82 ± 0.65 (0.28 ± 0.18) | 3.38 ± 0.55 (0.19 ± 0.11) | 2.19 ± 0.30 (0.09 ± 0.05) | 0.98, 0.35 | 0.68, 0.09 |
T1/2 (h) | 5.7 ± 2.2 | 4.2 ± 1.0 | 4.0 ± 0.9 | 3.0 ± 0.2 | 3.5, 2.9 | 3.2, 1.8 |
CL/F, CL (ml/h/kg) | 60 ± 16 | 82 ± 6.9 | 77 ± 11 | 101 ± 4.1 | 40, 110 | 50, 180 |
Vs/F, Vs (l/kg) | 0.5 ± 0.1 | 0.5 ± 0.1 | 0.5 ± 0.0 | 0.5 ± 0.1 | 0.2, 0.4 | 0.2, 0.4 |
MRT (h) | 8.5 ± 2.3 | 6.4 ± 1.1 | 5.9 ± 0.5 | 5.3 ± 0.6 | 4.7, 2.6 | 4.3, 1.9 |
Fc | 93% | 92% | 99% | 77% | NA | NA |
Cmax/C24 (C8 i.v.) | 15 | 30 | 47 | 90 | 7, 13 | 9, 48 |
CLR (ml/h/kg),% totald | ND | ND | ND | ND | 5.44, 20.5 | 7.31, 18.8 |
CLIE (ml/h/kg),% totald,e | ND | ND | ND | ND | 17.2, 52.2 (43-47%) | 31.2, 133 (62-74%) |
CL(biliary+met) (ml/h/kg),% total | ND | ND | ND | ND | 17.3, 37.3 | 11.5, 28.4 |
AC, activated charcoal; AUC, area under the plasma concentration versus time curve; CL, clearance; F, bioavailability; MRT, mean residence time; NA, not available; ND, not determined.
↵a Clast was last detectable time point for i.v. dosing or last determined time point for oral dosing.
↵b Both C8 and C24 were listed for oral administration.
↵c Bioavailability might be overestimated because the AUC values of bile-duct cannulated animals were used.
↵d Clearance was estimated from urinary dose recovery from 0-72 hour collections.
↵e The protein binding of apixaban in dog plasma was 92%, therefore, glomerular filtration rate ×Fu = 368×0.08 = 29.4 ml/h/kg.