In animal models, apixaban was well absorbed in dogs, chimpanzees, and rats. In human, oral bioavailability is approximately 50%.27 Apixaban reaches aromatase peak concentration approximately 3 hours after the oral administration, while half life is around 12 hours. It is predominantly eliminated through metabolic pathways and nonrenal mechanism. Less than 3% of the dose was excreted in bile collected between 3 and 8 hours postadministration.28 These data suggested that biliary excretion was a minor elimination pathway. Approximately 25% of apixaban was excreted in urine, which paralleled the disappearance of apixaban in plasma, which indicated that renal excretion was one of the significant routes of apixaban elimination.28,29 Apixaban is metabolized via the CYP3A4 system. Thus, coadministration of potent inhibitors of this enzyme, including macrolide antibiotics, protease inhibitors, and azole antifungal agents, should be avoided.30 Clinical Development Currently, apixaban has been evaluated for various indications for arthrosclerosis and thromboembolic diseases, including prevention and treatment of VTE, prevention of stroke in patients with atrial fibrillation, and prevention of clopidogrel cardiovascular events in ACS.Venous thromboembolism prophylaxis. The first completed phase II trial on the thromboprophylaxis after knee arthroplasty was the APROPOS trial.31 In this multicenter, double blinded study, approximately 1200 patients who had elective knee replacement were enrolled.
These patients were randomized to receive VEGFR signaling pathway either 1 of the 6 different dosages of apixaban or current guideline recommended enoxaparin/adjusted dose of warfarin. Patients received the assigned treatment for 10 to 14 days. At the end of the following period, mandatory venography was performed. The primary outcome was a composite of VTE and all cause mortality during treatment. The results showed that patients in apixaban group had lower primary outcome rates than the other counterparts. Apixaban regimens demonstrated relative risk reductions from 21% to 69% when compared to enoxaparin and 53% to 83% when compared to warfarin, suggesting this drug has a wide therapeutic window. In addition, there is no statistically high throughput screening significant dose response. On the contrary, there was a significant dose effect on total bleeding rates, regardless of daily or twice daily dosing.
All 4 major bleeding events that required surgical intervention were in patients receiving 20 mg of apixaban daily. Therefore, a total daily dose of 5 mg per day has a favorable benefit and bleeding risk profile which was selected for phase III study trial. In the phase III trial, ADVANCE 1,32 a multicenter, doubleblinded randomized trial, 3195 patients who were undergoing elective knee arthroplasty were randomly assigned to receive apixaban 2.5 mg twice a day or 30 mg enoxaparin sc every 12 hours for 10 to 14 days. After the treatment, patients were again evaluated with bilateral venography. The primary efficacy outcome was a composite of any DVT, nonfatal pulmonary embolism, and all cause mortality during treatment. The rate of primary outcome was 9.0% with apixaban as compared to 8.8% with enoxaparin. Although this study did not meet the prespecified noninferiority criteria for the primary efficacy outcomes.