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

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...

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Bibliographic Details
Published in:Clinical and applied thrombosis/hemostasis 2018-07, Vol.24 (5), p.724-733
Main Authors: Glund, Stephan, Gan, Guanfa, Moschetti, Viktoria, Reilly, Paul, Honickel, Markus, Grottke, Oliver, Van Ryn, Joanne
Format: Article
Language:English
Subjects:
Animals
Antibodies, Monoclonal, Humanized - metabolism
Antibodies, Monoclonal, Humanized - pharmacokinetics
Anticoagulants
Blood Coagulation - drug effects
Dabigatran - metabolism
Dabigatran - pharmacokinetics
Humans
Kidney - metabolism
Kidneys
Monoclonal antibodies
Original
Pharmacology
Rats
Renal Elimination
Renal Insufficiency
Swine
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Summary: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.
ISSN:1076-0296
1938-2723
DOI:10.1177/1076029618755947