Effect of Age and Renal Function on Idarucizumab Pharmacokinetics and Idarucizumab-Mediated Reversal of Dabigatran Anticoagulant Activity in a Randomized, Double-Blind, Crossover Phase Ib Study.
Idarucizumab is an antibody fragment that specifically reverses dabigatran-mediated anticoagulation. Safety, pharmacokinetics and pharmacodynamics of idarucizumab were investigated in dabigatran-treated, middle-aged, elderly and renally impaired volunteers with characteristics similar to patients receiving anticoagulant therapy.



In this randomized, double-blind, crossover study, 46 subjects (12 middle-aged, 45-64 years; 16 elderly, 65-80 years; and 18 with mild or moderate renal impairment) received dabigatran etexilate (DE; 220 or 150 mg twice daily) for 4 days. Idarucizumab doses of 1, 2.5 and 5 g or 2 × 2.5 g 1 h apart, or placebo, were administered as a rapid (5 min) infusion ~2 h after DE at steady state.



Dabigatran-prolonged diluted thrombin time, ecarin clotting time and activated partial thromboplastin time were reversed to baseline immediately after idarucizumab infusion in all groups. Reversal was sustained with doses ≥2.5 g. Idarucizumab was well tolerated under all conditions. No impact of age on idarucizumab pharmacokinetics was observed; however, subjects with mild or moderate renal impairment demonstrated increased exposure (up to 84 %), decreased clearance and prolonged (by up to 49 %) initial half-life of idarucizumab compared with healthy middle-aged subjects.



Impaired renal function was associated with increased exposure and decreased clearance of idarucizumab. Idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulant activity, and was safe and well tolerated in middle-aged, elderly and renally impaired volunteers. The results support the clinical use of a 5 g dose of idarucizumab.



http://www.clinicaltrials.gov . Unique identifier: NCT01955720.
Translational Medicine and Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Birkendorfer Straße 65, 88397, Biberach an der Riss, Germany. stephan.glund@boehringer-ingelheim.com.
Stephan
S
Glund
Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach an der Riss, Germany.
Joachim
J
Stangier
Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach an der Riss, Germany.
Joanne
J
van Ryn
Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach an der Riss, Germany.
Michael
M
Schmohl
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany.
Viktoria
V
Moschetti
Clinical Pharmacology Unit, SGS Life Science Services, Antwerp, Belgium.
Wouter
W
Haazen
Clinical Operations, SCS Boehringer Ingelheim Comm V, Brussels, Belgium.
Marina
M
De Smet
Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach an der Riss, Germany.
Dietmar
D
Gansser
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
Stephen
S
Norris
Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach an der Riss, Germany.
Benjamin
B
Lang
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
Paul
P
Reilly
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany.|Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.
Jörg
J
Kreuzer
D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D000991:Antithrombins / Q000494:pharmacology*; D019540:Area Under Curve; D001777:Blood Coagulation / Q000187:drug effects*; D018592:Cross-Over Studies; D000069604:Dabigatran / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006207:Half-Life; D006801:Humans; D007677:Kidney Function Tests; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D051437:Renal Insufficiency / Q000378:metabolism; D013997:Time Factors
D061067:Antibodies, Monoclonal, Humanized; D000991:Antithrombins; C000594745:idarucizumab; D000069604:Dabigatran