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Apixaban in patients on hemodialysis: a single dose pharmacokinetics study.

BACKGROUND
Apixaban, a direct oral anticoagulant inhibiting factor Xa, has been proven to reduce the risk of atrial fibrillation-related stroke and thrombo-embolism in patients with mild to moderate renal insufficiency. Patients on renal replacement therapy, however, were excluded from randomized controlled trials. Therefore, uncertainty remains concerning benefits, dosing and timing of intake in hemodialysis population.


METHODS
We conducted a phase II pharmacokinetics study in which twenty-four patients on maintenance hemodialysis were given a single dose (2.5 mg or 5 mg) of apixaban, either 30 minutes before or immediately after dialysis on the mid-week dialysis day.


RESULTS
Apixaban 5 mg resulted in higher AUC0-48 in comparison to 2.5 mg, although significance could only be reached for dosing pre-dialysis (2.5 mg vs. 5 mg, P = 0.008). In line, peak concentrations (Cmax) after dosing pre-dialysis were significantly higher in the 5 mg than in the 2.5 mg groups (P = 0.02). In addition, dialysis resulted in significant reduction of drug exposure. AUC0-48 pre-dialysis were on average 48 percent (2.5 mg) and 26 percent (5 mg) lower than the AUC0-48 post-dialysis, in line with Cmax. As a result, a dose of 2.5 mg post-dialysis and a dose of 5 mg pre-dialysis resulted in similar AUC0-48. In contrast, significant differences were found between the 5 mg group post-dialysis and the 2.5 mg group pre-dialysis (P = 0.013).


CONCLUSIONS
Our data suggest that exposure to apixaban in patients in maintenance hemodialysis is not only dependent on drug dose but also on timing of intake relative to the hemodialysis procedure.