The Measure of Plasma Concentrations Is Crucial in Managing Dabigatran Treatment in Non-Valvular Atrial Fibrillation
Authors: Iosub Diana , Trotti Rosa , Piovella Franco 
Published: November 2019

Abstract
One of the most popular features utilized to promote direct oral anticoagulants diffusion in stroke prevention in non-valvular atrial fibrillation is that these drugs do not require monitoring of their anticoagulant activity or plasma level measurements. We believe that there are clinical scenarios in which monitoring can help guide clinical management. Here we describe a clinical case in which close monitoring of thrombin inhibitor dabigatran peak plasma levels helped in maintaining the patient drug administration schedule, despite the interference of mirabegron, a beta-3 adrenergic agonist, utilized for the symptomatic treatment overactive bladder (OAB) syndrome, and of amiodarone, an effective and commonly prescribed antiarrhythmic drug. These P-glycoprotein (P-gp) inhibitors drugs may increase the blood levels and effects of dabigatran. Combining these medications may increase the risk of bleeding complications and anemia, especially when associated to mild to moderate renal insufficiency.
Dabigatran etexilate is a pro-drug that has a low (3%-7%) bioavailability. Once dabigatran etexilate is absorbed, the pro-drug is hydrolyzed to the active drug, dabigatran, by carboxylesterases in the bloodstream. Dabigatran etexilate is a substrate of the efflux transporter P-gp, but dabigatran, the active drug, is not. P-gp is present on the luminal side of absorptive cells in the small intestine and takes drug molecules from the cell cytoplasm and transports them back into the intestinal lumen for excretion. An inhibitor of P-gp, as mirabegron or amiodarone, will increase bioavailability of a P-gp substrate by reducing drug efflux.
Our patients suffers from persistent non-valvular atrial fibrillation, complicated by ischemic stroke. He has been assigned a dabigatran 150 mg b.i.d. treatment in may 2014. His creatinine clearance was 75 mL/min. One month later, due to OAB syndrome, he started mirabegron, a drug which might potentially increase the risk of bleeding and which generally causes to stop dabigatran administration. We decided instead to set up a monitoring plan, utilizing plasma-diluted thrombin time to measure dabigatran concentrations. Calibration material consisted of pooled normal plasma with known quantities of dabigatran. By using this calibration material, we constructed a dose-response curve ranging from 0 to 500 ng/mL of dabigatran. An examination of the published literature of the pharmacology of dabigatran indicated that the expected peak steady-state concentration of dabigatran in patients with atrial fibrillation (150 mg, 2 times daily) was approximately 180 ng/mL with a trough of approximately 90 ng/mL (12 hours after last dose).
After 4 weeks of mirabegron administration, dabigatran plasma trough level of our patient was 126.4 ng/mL. We therefore decided not to modify the 150 mg b.i.d. treatment.
Three weeks later, patient suffered from acute cardiac failure associated to a creatinine clearance reduction to 41 mL/min. As a consequence, mirabegron treatment was stopped. At this point, dabigatran plasma trough level was 148.6 ng/mL. Again, we decided not to modify the 150 mg b.i.d. treatment.
Six weeks later, due to an elevated cardiac rate (140/min) a treatment with 300 mg o.d. of amiodarone was started. A week later dabigatran plasma trough level was 219.6 ng/mL, with a creatinine clearance of 58mL/min. We decided then to reduce the administration of dabigatran to 110 mg twice daily.
After two weeks, dabigatran plasma trough level lowered to 120.2 ng/mL.
Our patient is still on dabigatran treatment which has so far never been stopped.
At this time, studies addressing the correlation of dabigatran concentration with risk of bleeding (overdose) or breakthrough thrombosis (underdosing) are unavailable. The lack of such studies currently limits the predictive power of the plasma-diluted thrombin time to determine hemorrhage/thrombosis risk. However, we believe that in situations like our patient’s the adoption of this assay would be a valuable tool to aid adjusting dabigatran treatment. With access to appropriate pharmacodynamic and pharmacokinetic data and relevant calibration material, the plasma–diluted thrombin time assay can easily be applied for use in the monitoring dabigatran etexilate.

Disclosures
No relevant conflicts of interest to declare.