Apixaban Pharmacokinetics at Steady State in Hemodialysis Patients

Abstract

It is unclear whether warfarin is protective or harmful in patients with ESRD and atrial fibrillation. This state of equipoise raises the question of whether alternative anticoagulants may have a therapeutic role. We aimed to determine apixaban pharmacokinetics at steady state in patients on hemodialysis. Seven patients received apixaban 2.5 mg twice daily for 8 days. Blood samples were collected before and after apixaban administration on days 1 and 8 (nondialysis days). Significant accumulation of the drug was observed between days 1 and 8 with the 2.5-mg dose. The area under the concentration-time curve from 0 to 24 hours increased from 628 to 2054 ng h/ml (<0.001). Trough levels increased from 45 to 132 ng/ml (<0.001). On day 9, after a 2.5-mg dose, apixaban levels were monitored hourly during dialysis. Only 4% of the drug was removed. After a 5-day washout period, five patients received 5 mg apixaban twice daily for 8 days. The area under the concentration-time curve further increased to 6045 ng h/ml (=0.03), and trough levels increased to 218 ng/ml (=0.03), above the 90th percentile for the 5-mg dose in patients with preserved renal function. Apixaban 2.5 mg twice daily in patients on hemodialysis resulted in drug exposure comparable with that of the standard dose (5 mg twice daily) in patients with preserved renal function and might be a reasonable alternative to warfarin for stroke prevention in patients on dialysis. Apixaban 5 mg twice daily led to supratherapeutic levels in patients on hemodialysis and should be avoided.

Clinical Pharmacology of Oral Anticoagulants in Patients with Kidney Disease

“…Drug levels comparing day 5 versus day 8 suggested that a steady state had been reached. Despite that it still would be of interest to examine levels with a longer duration of exposure (52).…”

Comparison of the Safety and Effectiveness of Apixaban versus Warfarin in Patients with Severe Renal Impairment: An Alternative Viewpoint

“…New steady‐state pharmacokinetic evidence evaluating NVAF patients undergoing thrice‐weekly 4‐hour hemodialysis sessions has emerged, indicating apixaban 5 mg twice/day may lead to supratherapeutic apixaban levels (observed in two of five patients) . Apixaban 2.5 mg twice/day in the same five patients (average age 62 years, body mass index 32.9 kg/m 2 ) led to mean apixaban peak, trough, and area under the concentration‐time curve (AUC) levels comparable to the reference range determined in the ARISTOTLE trial . However, the authors also reported the 24‐hour AUC fell below the 10th percentile in three of five patients with the 2.5 mg twice/day dosage in the hemodialysis population .…”

“…Apixaban 2.5 mg twice/day in the same five patients (average age 62 years, body mass index 32.9 kg/m 2 ) led to mean apixaban peak, trough, and area under the concentration‐time curve (AUC) levels comparable to the reference range determined in the ARISTOTLE trial . However, the authors also reported the 24‐hour AUC fell below the 10th percentile in three of five patients with the 2.5 mg twice/day dosage in the hemodialysis population . The authors concluded that while apixaban may be a reasonable alternative in hemodialysis, the 5 mg twice/day dosage should be avoided …”

Successful treatment of heparin‐induced thrombocytopenia with apixaban in a patient with chronic kidney disease requiring hemodialysis

“…Among DOACs, apixaban is the least dependent on renal clearance of the direct factor Xa inhibitors and might be the one with the smallest bleeding risk 4. As a matter of fact, there is some pharmacokinetic evidence to support the use of an adjusted dose of apixaban in patients on HD 5. However, individuals with severely impaired kidney function and concomitant HIT are underrepresented in the medical literature.…”