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Clin Pharmacokinet. 2017 Jan;56(1):41-54. doi: 10.1007/s40262-016-0417-0.

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.

Author information

1
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.
2
Boehringer Ingelheim Pharma GmbH & Co. KG, 88397, Biberach an der Riss, Germany.
3
Boehringer Ingelheim Pharma GmbH & Co. KG, Ingelheim am Rhein, Germany.
4
Clinical Pharmacology Unit, SGS Life Science Services, Antwerp, Belgium.
5
Clinical Operations, SCS Boehringer Ingelheim Comm V, Brussels, Belgium.
6
Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA.
7
Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.

Abstract

BACKGROUND AND OBJECTIVES:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

CLINICAL TRIAL REGISTRATION:

http://www.clinicaltrials.gov . Unique identifier: NCT01955720.

PMID:
27317414
PMCID:
PMC5222901
DOI:
10.1007/s40262-016-0417-0
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Compliance with ethical standardsFundingThis study was funded by Boehringer Ingelheim Pharma GmbH & Co. KG. Medical writing assistance, supported financially by Boehringer Ingelheim Pharma GmbH & Co. KG, was provided by PAREXEL during the preparation of this article.Conflicts of interestStephan Glund, Joachim Stangier, Joanne van Ryn, Michael Schmohl, Viktoria Moschetti, Dietmar Gansser, Benjamin Lang and Jörg Kreuzer are employees of Boehringer Ingelheim Pharma GmbH & Co. KG. Wouter Haazen was the principal investigator of this trial and is an employee of SGS Life Science Services, the contract research organization that was funded by Boehringer Ingelheim Pharma GmbH & Co. KG to perform the clinical trial. Marina De Smet is an employee of SCS Boehringer Ingelheim. Stephen Norris and Paul Reilly are employees of Boehringer Ingelheim Pharmaceuticals, Inc.Ethical approvalAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

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