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

被引:55
作者
Glund, Stephan [1 ]
Stangier, Joachim [2 ]
van Ryn, Joanne [2 ]
Schmohl, Michael [2 ]
Moschetti, Viktoria [3 ]
Haazen, Wouter [4 ]
De Smet, Marina [5 ]
Gansser, Dietmar [2 ]
Norris, Stephen [6 ]
Lang, Benjamin [2 ]
Reilly, Paul [6 ]
Kreuzer, Joerg [3 ,7 ]
机构
[1] Boehringer Ingelheim Pharma GmbH & Co KG, Translat Med & Clin Pharmacol, Birkendorfer Str 65, D-88397 Biberach, Germany
[2] Boehringer Ingelheim Pharma GmbH & Co KG, D-88397 Biberach, Germany
[3] Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany
[4] SGS Life Sci Serv, Clin Pharmacol Unit, Antwerp, Belgium
[5] SCS Boehringer Ingelheim Comm V, Clin Operat, Brussels, Belgium
[6] Boehringer Ingelheim Pharmaceut Inc, 90 E Ridge POB 368, Ridgefield, CT 06877 USA
[7] Heidelberg Univ, Fac Med, Heidelberg, Germany
关键词
NONVALVULAR ATRIAL-FIBRILLATION; ACUTE VENOUS THROMBOEMBOLISM; WARFARIN; SAFETY; TOLERABILITY; VOLUNTEERS; ANTIDOTE; EFFICACY; TRIAL; CARE;
D O I
10.1007/s40262-016-0417-0
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 x 2.5 g 1 h apart, or placebo, were administered as a rapid (5 min) infusion similar to 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.
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页码:41 / 54
页数:14
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