Dialysis based approaches can provide rapid removal of dabigatran in cases of emergency due to its low protein binding of ∼35%. However the in vitro properties of these filtration devices have not yet been characterized in detail. This study in the porcine system (both in vitro and in vivo) was performed to evaluate dabigatran elimination by hemodialysis and activated charcoal perfusion as compared to normal renal elimination.
Porcine blood (5L) was supplemented with 1000 ng/mL dabigatran and circulated through an circuit of tubing allowing attached to an activated charcoal filter (Absorba 300 C, Gambro). Further supplementation of dabigatran allowed the determination of maximum binding capacity of the filter. A similar set up was used to also test dialysis (Polyflux 140H, Gambro) and determine the dependence of the flow rate on dabigatran removal. Dialysate flow rates were increased up to 500 ml/min. Anesthetized pigs (Domestic swine, female, ∼60 kg) were attached to an activated charcoal column or a High-Flux hemodialysis filter with a blood flow rate of 200 ml/min. Animals were given an initial i.v. infusion of dabigatran (7.5 mg in 15 min) and then reduced to 5 mg/hr to achieve steady state dabigatran over 1hr. Infusion was then stopped and elimination methods were applied over 4 hrs. An observation time of 1 hr followed. Dabigatran plasma levels were quantitated with diluted thrombin time. Preliminary settings/flow rates were obtained in vitro using 5L citrated porcine whole blood exposed to different AC or HD conditions.
Activated charcoal completely removed dabigatran within 1 hr from the 5L whole blood supplemented with 1000 ng/mL dabigatran, with a clearance rate of 100%. By repeatedly reapplying dabigatran, it was shown the active charcoal filter had a maximum binding capacity of ∼30 mg drug. Upon saturation there was no further clearance of dabigatran. Hemodialysis removed dabigatran with increasing clearance rates depending on dialysate flow rates (100 ml/min-35%, 200 ml/min-60%, 300 ml/min-65%) reaching a plateau of ∼65%. Further increases of dialysate flow to 500 ml/min had no further effect on drug clearance.
Initial plasma levels of dabigatran ranged between 200–450 ng/mL after 60 min infusion in pigs. Exposure to activated charcoal or hemodialysis (dialysate flow 300 ml/min) resulted in 75–80% reduction in circulating dabigatran after 1 hr as compared to ∼25% reduction untreated controls after 1 hr. After 2 hrs dabigatran levels were below the detection limit using both elimination methods.
Dabigatran can effectively be removed from the circulation in this in vivo porcine model using dialysis based approaches, which results in a restoration of blood coagulation. Active charcoal perfusion was fast and effectively removed dabigatran, but may be saturated if dabigatran plasma levels are too high (human body load for 150 mg dose in steady state is ∼14g). Stationary hemodialysis with sufficiently high dialysate flows achieves similar results in this model without saturation limitations; however, the set up for dialysis is much more specialized than the simpler approach of activated charcoal filtration.
Formella:Boehringer Ingelheim: Employment. Clemens:Boehringer Ingelheim (Anticoagulant Therapy): Employment. van Ryn:Boehringer Ingelheim: Employment. Schenk:Boehringer Ingelheim: Research Funding.
Asterisk with author names denotes non-ASH members.