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

Glund S,Stangier J, van Ryn J, et al.
Clin Pharmacokinet 2016; published online ahead of print

Background

Dabigatran is a direct thrombin inhibitor, indicated for the prevention and treatment of thromboembolic events in patients with atrial fibrillation (AF) [1–3]. Immediate reversal of the anticoagulation effect could be achieved with the intravenous use of idarucizumab in young and healthy volunteers [4-7].
Idarucizumab is an antibody fragment that may be useful in elderly AF patients with renal dysfunction, or AF patients who must undergo urgent surgery, or have a major bleeding event, in which case it is important to re-start anticoagulation as soon as possible after reversal, in order to prevent stroke.
In this randomised, double-blind, cross-over study, the pharmacodynamics (PD) of the reversal of dabigatran anticoagulant (oral prodrug is dabigatran etexilate, DE) effect by idarucizumab was evaluated, in 46 middle-aged volunteers vs. healthy elderly, and mild (60-90) or moderately (30-60) renally impaired (RI) volunteers. All but the moderate RI group, received low or high doses which were variable among groups; 2.5 or 5 gr for middle-aged, 1 or 5 gr for elderly, 1 or 5 gr for 60-90 RI and 2x2.5 gr for 30-60 RI volunteers.

Main results

Dabigatran etexilate (DE):

• After 2 hours, steady-state plasma levels of unbound dabigatran were 170 ng/mL in middle-aged volunteers vs. 140 and 220 ng/mL in volunteers with RI 60-90 respectively 30-60.
• Resulted in a 1.8-, 3-, 2.2-fold increase of diluted thrombin time (dTT), ecarin clotting time (ECT) and activated partial thromboplastin time (aPTT) in middle-aged patients.
• Resulted in a 3.1-, 3.6-, 2.2-fold increase of dTT, ECT, aPTT in elderly vs. middle-aged volunteers

Idarucizumab (low or high doses) resulted in an immediate reduction of the dabigatran-prolonged coagulation times to baseline levels. This effect was sustained for 24 h:

• The idarucizumab plasma concentration–time profile in elderly volunteers was very similar to that of middle-aged volunteers.
• Idarucizumab exposure (AUC) was similar in middle-aged and elderly patients but increased in 60-90 and 30-60 RI patients (P=0.002 and P<0.0001 respectively).
• Unbound dabigatran plasma concentrations decreased evenly between all groups  <1ng/mL.
• The initial half time was equal between middle-aged and elderly volunteers but prolonged in both RI groups when compared with the middle-aged group P=0.0099 for 60-90 and P=0.0003 for 30-60).
• Clearance was equal between middle-aged and elderly volunteers but decreased in 60-90 and 30-60 RI patients compared to the middle-aged group (P=0.002 and P<0.0001 respectively).
• The 1gr doses in elderly and 60-90 RI volunteers resulted in a partial return of dabigatran anticoagulation after 2 hours, which was not observed in middle-aged volunteers whom received 5 or 2.5 gr.
• All adverse events (46% for dabigatran, 30% for idarucizumab and 26% for placebo) were mild and independent of group.

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Conclusion

Pharmacodynamic data showed that idarucizumab resulted in immediate, complete and sustained reversal of dabigatran anticoagulant activity independent of age or renal function. Impaired renal function was associated with increased exposure and decreased clearance of idarucizumab. Idarucizumab effects were dose-dependent. All doses were safe and well tolerated.

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References

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