Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects

Abstract

Aim: Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban.

Method: This double-blind, randomized, placebo-controlled, parallel group, multiple dose escalation study was conducted in six sequential dose panels - apixaban 2.5, 5, 10 and 25 mg twice daily and 10 and 25 mg once daily- with eight healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT).

Results: Forty-eight subjects were randomized and treated (apixaban, n = 36; placebo, n = 12); one subject receiving 2.5 mg twice daily discontinued due to AEs (headache and nausea). No dose limiting AEs were observed. Apixaban maximum plasma concentration was achieved ~3 h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by day 3, with an accumulation index of 1.3-1.9. Peak : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration-time profile.

Conclusion: Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures.

Keywords: anticoagulant/thrombolytic drugs; apixaban; cardiovascular pharmacology; coagulation/fibrinolysis; pharmacokinetics.

© 2013 Bristol-Myers Squibb Co. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

Figures

Figure 1

Mean (+ SD) plasma apixaban concentration vs. time profiles on days 1 and 7 for (A) twice daily and (B) once daily dosing regimens. , 2.5 mg twice daily; , 5 mg twice daily; , 10 mg twice daily; , 25 mg twice daily; , 10 mg once daily; , 25 mg once daily

Figure 2

Mean (+ SD) apixaban plasma concentrations from day 1 to day 7 in subjects who received 5 mg twice daily or 10 mg once daily. , 5 mg twice daily; , 10 mg once daily

Figure 3

Mean international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT) values over time for day 1 to day 7. , 2.5 mg twice daily; , 5 mg twice daily; , 10 mg twice daily; , 25 mg twice daily; , 10 mg once daily; , 20 mg once daily; , pooled placebo

Figure 4

International normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT) vs. apixaban plasma concentration for individual patients with regression lines. C, apixaban concentration (ng ml−1)