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 (P<0.001). Trough levels increased from 45 to 132 ng/ml (P<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 (P=0.03), and trough levels increased to 218 ng/ml (P=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.

Keywords: apixaban; atrial fibrillation; hemodialysis; pharmacokinetics.

Figure 1.

Apixaban PK parameters with the 2.5-mg twice daily dose on days 1 and 8, showing significant accumulation of the drug.

Figure 2.

Effect of hemodialysis on apixaban levels. The solid line shows apixaban levels during the first 4 hours after drug administration (2.5 mg) on day 8 (nondialysis day). The dotted line shows apixaban levels during hemodialysis on day 9. The dialysis session started immediately after the drug administration (2.5 mg) and lasted for 4 hours.

Figure 3.

Comparison of the PK parameters at steady state (i.e., after 8 days of apixaban administration) achieved with the reduced dose (2.5 mg twice daily) and with the standard dose (5 mg twice daily) of apixaban. The dotted lines represent the 10th and 90th percentiles of the predicted levels for the 5-mg twice daily dose in patients with preserved renal function (5th and 95th percentiles for C_max). AUCss, area under the concentration-time curve at steady state; bid, twice daily.

Figure 4.

Schematic presentation of study interventions (phases 1–3). Phase 1: apixaban exposure after a 2.5 mg single dose and at steady state (day 8). Phase 2: effect of hemodialysis on apixaban concentration at steady state. Phase 3: apixaban exposure at steady state with a 5 mg bid dose. Bid, twice daily.