A ATHAVALE1,2, N JAMSHIDI2, D ROBERTS3,4,5
1Department of Renal Medicine, Concord Repatriation General Hospital, Concord, Australia, 2Drug Health Services and Clinical Pharmacology and Toxicology, Royal Prince Alfred Hospital, Camperdown, Australia, 3Department of Nephrology and Transplantation, St Vincent’s Hospital, Sydney, Australia, 4Department of Clinical Pharmacology and Toxicology, Sydney, Australia, 5St Vincent’s Clinical School, University of New South Wales, Sydney, Australia
Aim: To evaluate the impact of impaired kidney function on accumulation of dabigatran and effectiveness of idarucizumab.
Background: The monoclonal antibody fragment idarucizumab binds dabigatran to reverse dabigatran-induced anticoagulation. The standard 5 g dose of idarucizumab was based on data from health volunteer studies with normal kidney function. Dabigatran is 80% eliminated renally, therefore kidney impairment can lead to accumulation of dabigatran and rebound in dabigatran activity following idarucizumab.
Methods: A systematic literature search was performed to identify cases of dabigatran rebound following idarucizumab. A two compartment pharmacokinetic model for dabigatran was developed to explore the impact of kidney function on efficacy of 5 g idarucizumab.
Results: Ninety-seven articles were suitable for inclusion, representing 240 cases of idarucizumab use. Thirty-three cases reported rebound in dabigatran following idarucizumab. The mean glomerular filtration rate was 36 mL/min in cases where dabigatran rebound occurred. In comparison, where no rebound was reported, mean glomerular filtration rate was 65 mL/min (p < 0.0001). Reduced glomerular filtration rate was associated with a significant increase in median plasma dabigatran concentrations. Median pre-idarucizumab plasma dabigatran concentrations were 101.5 ng/mL, 205.1 ng/mL and 736 ng/mL for glomerular filtration rates greater than 60mL/min, 30 – 60 mL/min and less than 30 mL/min respectively (p = 0.0004).
When dosing dabigatran 150 mg twice daily, pharmacokinetic modelling predicted an incomplete response to idarucizumab 5 g after approximately 72 hours when glomerular filtration rate was less than 30 mL/min.
Conclusion: Impaired kidney function is associated with accumulation of dabigatran. Acute impairment of kidney function for as little as 72 hours may result in rebound dabigatran activity which could require repeat idarucizumab administration.
Akshay is an advanced physician trainee in clinical pharmacology and nephrology in New South Wales, Australia.