title: Evaluation of the immunogenicity of the dabigatran reversal agent idarucizumab during Phase I studies.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Norris
authors.affiliation: SGS Life Sciences Clinical Research Services, Clinical Pharmacology Unit, Antwerp, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Ramael
authors.affiliation: Department of Internal Medicine, Souseikai Global Clinical Research Center, Sumida Hospital, LTA Medical Corp, Tokyo, Japan.
authors.forename: Ippei
authors.initials: I
authors.lastname: Ikushima
authors.affiliation: SGS Life Sciences Clinical Research Services, Clinical Pharmacology Unit, Antwerp, Belgium.
authors.forename: Wouter
authors.initials: W
authors.lastname: Haazen
authors.affiliation: Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Harada
authors.affiliation: Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Moschetti
authors.affiliation: Nippon Boehringer Ingelheim Co. Ltd, Tokyo, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Imazu
authors.affiliation: Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Reilly
authors.affiliation: Boehringer Ingelheim GmbH & Co. KG, Biberach an der Riß, Germany.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Lang
authors.affiliation: Boehringer Ingelheim GmbH & Co. KG, Biberach an der Riß, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Stangier
authors.affiliation: Boehringer Ingelheim GmbH & Co. KG, Biberach an der Riß, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Glund
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology* / Q000494:pharmacology* / Q000627:therapeutic use; D057134:Antibodies, Neutralizing / Q000097:blood; D000991:Antithrombins / Q000009:adverse effects*; D001777:Blood Coagulation / Q000187:drug effects*; D000069604:Dabigatran / Q000009:adverse effects*; D004311:Double-Blind Method; D000939:Epitopes / Q000276:immunology; D064368:Healthy Volunteers; D006470:Hemorrhage / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D049449:Luminescence; D008875:Middle Aged; D051437:Renal Insufficiency / Q000097:blood; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000991:Antithrombins; D000939:Epitopes; C000594745:idarucizumab; D000069604:Dabigatran
keywords: antibodies; anticoagulants; coagulation; immunology; pharmacokinetics