Table 4.
Comparison of pharmacokinetic and dispositional properties of apixaban in animal species and humans [48–57]
| Parameters | Human | Rabbit | Rat | Dog | Chimpanzee | |||||
|---|---|---|---|---|---|---|---|---|---|---|
| Dose route | IV | PO | IV | PO | IV | PO | IV | PO | IV | PO |
| Dose (mg or mg/kg) | 2.5 | 2.5 | 2.5 | 10 | 0.5 | 2.0 | 0.2 | 0.5 | 0.2 | 0.5 |
| Cmax (μg/ml) | NA | 0.04–0.05 | 10.7 | 0.014 | NA | 1.1 | NA | 1.1 | NA | 1.6 |
| Tmax (h) | NA | 1–4 | NA | 1 | NA | 0.5 | NA | 1.0 | NA | 2.0 |
| AUC0-24 (μg h/ml) | 0.7–0.9 | 0.41–0.45 | 1.66 | 0.05 | 2.0 | 2.7 | 3.9 | 8.0 | 10.1 | 13.6 |
| CLTp or CL/F (ml/min/kg) | 0.83 | 1.2 | 42.5 | NA | 4.3 | NA | 0.87 | NA | 0.30 | NA |
| Vd (l/kg) | 0.31 | 0.30 | 0.88 | NA | 0.31 | NA | 0.30 | NA | 0.17 | NA |
| T1/2 (h) | 5–9 | 8–13 | 0.6 | NA | 1.9 | 3.2 | 5 | 5.8 | 6.8 | 4.9 |
| MRT (h) | NA | – | 0.36 | 11.3 | 1.2 | 3.2 | 5.8 | 8.0 | 9.6 | 8.3 |
| Oral bioavailability F% | NA | 51 | NA | 3 | NA | 34 | NA | 88 | NA | 51 |
| Protein binding (%) | 86.8–93.2 | 61.5–66.2 | 95.2–96.4 | 91.0–93.7 | 94.3–95.1 | |||||
| Renal elimination (% of dose) | 25–28 (22–24 as parent) | 25 for IV and 2 for PO (10 and <0.5 parent) | 13.4 (12.1 as parent) | 8.8 (7.2 as parent) | ND | |||||
| % of dose excreted as parent | ~56 | ~22–40 | 87.4 | 65.8 | ND | |||||
| Metabolic pathways | O-Demethylation and hydroxylation | O-Demethylation and hydroxylation | O-Demethylation and hydroxylation | O-Demethylation and hydroxylation | ND | |||||
| Circulating inactive metabolite | O-Demethyl apixaban sulfate | O-Demethyl apixaban glucuronide | Minor O-demethyl apixaban sulfate | Minor O-demethyl apixaban sulfate | ND | |||||
A value range was reported for some kinetic parameters. Protein binding was 57.6–63.5 and 33.5–56.5% in monkey and mouse serum at apixaban concentrations of 0.46–4.59 μg/ml
Protein binding in human serum albumin and alpha-1 acid glycoprotein was 66 and 9%, respectively
Blood-to-plasma ratio was 1.03 and 0.9 in dog and human, respectively
Urinary/fecal elimination (%) following administration of [14C]apixaban was 15.2/83.9 (0–48 h; mouse PO), 13.4/74.0 (0–168 h; rat PO), 20.7/12.7 (0–24 h; rat IV), 1.76/54.3 (0–48 h; rabbit PO), 24.8/62.4 (0–48 h; rabbit IV), 8.8/73.7 (0–168 h; dog PO) and 24.5/56.0 (0–292 h; human PO). Urinary/fecal/bile elimination was 10.5/69.8/2.6 (0–48 h; rat PO) and 28.8/46.7/2.44 (0–216 h, 3–8 h for bile collection; human PO)
All metabolites represented 1.51% (urine)/10.7% (feces) and 15.4% (urine)/50.4% (feces) of dose in urine and feces of mouse and rabbit following PO and IV administration of [14C]apixaban, respectively
Cmax maximum plasma concentration, Tmax time to Cmax, AUC0-24 area under the plasma concentration–time curve from time 0–24 h, CLTp total plasma clearance, Vd volume of distribution, T1/2 terminal elimination half-life, MRT mean residence time, F% oral bioavailability, NA not applicable, ND not determined