Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies

Br J Clin Pharmacol. 2017 Aug;83(8):1815-1825. doi: 10.1111/bcp.13269. Epub 2017 Apr 6.


Aims: Idarucizumab, a humanized monoclonal anti-dabigatran antibody fragment, is effective in emergency reversal of dabigatran anticoagulation. Pre-existing and treatment-emergent anti-idarucizumab antibodies (antidrug antibodies; ADA) may affect the safety and efficacy of idarucizumab. This analysis characterized the pre-existing and treatment-emergent ADA and assessed their impact on the pharmacokinetics and pharmacodynamics (PK/PD) of idarucizumab.

Methods: Data were pooled from three Phase I, randomized, double-blind idarucizumab studies in healthy Caucasian subjects; elderly, renally impaired subjects; and healthy Japanese subjects. In plasma sampled before and after idarucizumab dosing, ADA were detected and titrated using a validated electrochemiluminescence method. ADA epitope specificities were examined using idarucizumab and two structurally related molecules. Idarucizumab PK/PD data were compared for subjects with and without pre-existing ADA.

Results: Pre-existing ADA were found in 33 out of 283 individuals (11.7%), seven of whom had intermittent ADA. Titres of pre-existing and treatment-emergent ADA were low, estimated equivalent to <0.3% of circulating idarucizumab after a 5 g dose. Pre-existing ADA had no impact on dose-normalized idarucizumab maximum plasma levels and exposure and, although data were limited, no impact on the reversal of dabigatran-induced anticoagulation by idarucizumab. Treatment-emergent ADA were detected in 20 individuals (19 out of 224 treated [8.5%]; 1 out of 59 received placebo [1.7%]) and were transient in ten. The majority had specificity primarily toward the C-terminus of idarucizumab. There were no adverse events indicative of immunogenic reactions.

Conclusion: Pre-existing and treatment-emergent ADA were present at extremely low levels relative to the idarucizumab dosage under evaluation. The PK/PD of idarucizumab appeared to be unaffected by the presence of pre-existing ADA.

Trial registration: ClinicalTrials.gov NCT01688830 NCT01955720 NCT02028780.

Keywords: antibodies; anticoagulants; coagulation; immunology; pharmacokinetics.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / immunology*
  • Antibodies, Monoclonal, Humanized / pharmacology*
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antibodies, Neutralizing / blood
  • Antithrombins / adverse effects*
  • Blood Coagulation / drug effects*
  • Dabigatran / adverse effects*
  • Double-Blind Method
  • Epitopes / immunology
  • Healthy Volunteers
  • Hemorrhage / chemically induced
  • Hemorrhage / drug therapy
  • Humans
  • Luminescence
  • Middle Aged
  • Renal Insufficiency / blood
  • Treatment Outcome
  • Young Adult


  • Antibodies, Monoclonal, Humanized
  • Antibodies, Neutralizing
  • Antithrombins
  • Epitopes
  • idarucizumab
  • Dabigatran

Associated data

  • ClinicalTrials.gov/NCT01688830
  • ClinicalTrials.gov/NCT01955720
  • ClinicalTrials.gov/NCT02028780