The Renal Elimination Pathways of the Dabigatran Reversal Agent Idarucizumab and its Impact on Dabigatran Elimination

Abstract

Idarucizumab, a humanized monoclonal antibody fragment (Fab), provides rapid and sustained reversal of dabigatran-mediated anticoagulation. Idarucizumab and dabigatran are mainly eliminated via the kidneys. This analysis aimed to characterize the renal elimination of idarucizumab and investigate the influence of idarucizumab on the pharmacokinetics (PK) of dabigatran and vice versa. Studies were conducted in 5/6 nephrectomized rats, in human volunteers with and without renal impairment, and in a porcine liver trauma model. In both rats and humans, renal impairment increased idarucizumab exposure and initial half-life but did not affect its terminal half-life. Urinary excretion of unchanged idarucizumab increased with increasing idarucizumab dose, suggesting saturation of renal tubular reuptake processes at higher doses. The PK of idarucizumab was unaffected by dabigatran. In contrast, idarucizumab administration resulted in redistribution of dabigatran to the plasma, where it was bound and inactivated by idarucizumab. Urinary excretion of dabigatran after administration of idarucizumab was delayed, but total dabigatran excreted in urine was unaffected. Idarucizumab and dabigatran were eliminated together via renal pathways.

Keywords: clinical pharmacokinetics; elimination; renal clearance.

Figure 1.

Mean (±SD) plasma concentration–time profiles of idarucizumab (A) and dabigatran (B) in rats with normal renal function after intravenous bolus administration (separately or together; n = 3 each group). SD indicates standard deviation.

Figure 2.

Geometric mean idarucizumab plasma concentration–time profiles after a single 5-minute infusion of 1 to 4 g idarucizumab with or without 220 mg dabigatran etexilate twice daily in healthy human volunteers.

Figure 3.

Mean (±SD) percentage of idarucizumab and dabigatran excreted into the urine after intravenous dosing of dabigatran (0.2 mg/kg) or idarucizumab (20 mg/kg) alone or together (dabigatran dosing followed by idarucizumab 15 minutes later) in rats with normal renal function. SD indicates standard deviation.

Figure 4.

Mean fraction (percentage of dose ± SEM) of dabigatran dose and idarucizumab dose excreted in urine in elderly (A), volunteers with mild RI (B), and moderate RI (C). Volunteers received idarucizumab or placebo 2 hours after the last dabigatran etexilate dose; urine collection time intervals are shown as time from the last dose of dabigatran etexilate. Elderly patients aged 65 to 80 years; creatinine clearance 60 to 90 mL/min for mild RI and 30 to 60 mL/min for moderate RI.

Figure 5.

Mean (±SD) cumulative percent of dose of dabigatran (A) and idarucizumab (B) excreted into the urine in 5/6 nephrectomized rats and in rats with normal renal function. SD indicates standard deviation.

Figure 6.

Mean changes in urinary volume (±SD) as a consequence of trauma-induced blood loss and its reversal with idarucizumab in a porcine trauma model (n = 3-7 per group). SD indicates standard deviation.

Figure 7.

Comparison of plasma concentration–time profiles of total dabigatran, active dabigatran, and idarucizumab after intravenous dosing with idarucizumab 15 minutes after dabigatran administration in a porcine trauma model. Idarucizumab was administered at doses of 30 mg/kg (A), 60 mg/kg (B), and 120 mg/kg (C); data points are mean values (±SD; n = 6 animals for each dose). SD indicates standard deviation.