Pharmacokinetics and Pharmacodynamics of the Direct Oral Thrombin Inhibitor Dabigatran in Healthy Elderly Subjects

Stangier, Joachim; Stähle, Hildegard; Rathgen, Karin; Fuhr, Reinhold

doi:10.2165/00003088-200847010-00005

Cited by 392 publications

(331 citation statements)

References 3 publications

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“…However, renal clearance of dabigatran decreases in patients with an acute or chronic decline in kidney function, resulting in a corresponding increase in half-life from about 13 hours in individuals with normal kidney function to 18, 28, and 34 hours in patients with CrCl=30-50 ml/min, CrCl,30 ml/min, and ESRD, respectively (22). Obviously, this increase leads to significantly higher serum concentrations and enhanced anticoagulant effects of dabigatran for a given dose in these individuals compared with individuals with normal kidney function (5,14,15,18). Although baseline kidney function was known only in cases 1, 2, and 4, all patients were presumed to have AKI, which likely explains their elevated dabigatran plasma concentrations on admission.…”

Section: Discussionmentioning

confidence: 99%

“…Dabigatran exhibits several physicochemical and pharmacokinetic properties that favor extracorporeal removal. Specifically, it is a small molecule with a molecular weight of approximately 630, it is predominantly (80%) excreted unchanged in the urine, and it displays relatively low protein binding of 26%-28% (2,5,22). Recent reports suggest that IHD clears dabigatran from the blood (16,(21)(22)(23)).…”

Section: Discussionmentioning

confidence: 99%

“…The drug has advantages over warfarin that make it appealing; namely, it is as effective as warfarin in preventing stroke in patients with nonvalvular atrial fibrillation with similar or lower bleeding risk (3,4). Also, because it normally exhibits a predictable pharmacokinetic-pharmacodynamic profile, it does not require routine monitoring (5)(6)(7). This finding has generated considerable enthusiasm among clinicians, evidenced by approximately 3.7 million dabigatran prescriptions dispensed by outpatient retail pharmacies to roughly 725,000 patients in the United States alone from the time of FDA approval in October of 2010 through August of 2012 (8).…”

Section: Introductionmentioning

confidence: 99%

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Extracorporeal Therapy for Dabigatran Removal in the Treatment of Acute Bleeding

Singh

Maw

Henry³

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Dabigatran is an oral direct thrombin inhibitor that is Food and Drug Administrationapproved for prevention of stroke in patients with atrial fibrillation. No antidote is available for reversal of dabigatran's anticoagulant effect. Despite limited clinical data, hemodialysis has been suggested as a strategy to remove dabigatran during acute bleeding. This work presents five cases, in which extracorporeal therapy was performed for dabigatran removal in acutely bleeding patients.Design, setting, participants, & measurements The series is comprised of five consecutive cases of patients receiving dabigatran 150 mg per os two times daily who were admitted with life-threatening bleeding between March of 2012 and January of 2013. Dabigatran plasma concentrations ranged from 149 to 1200 ng/ml. Treatment included administration of blood products to all patients and then, high-flux intermittent hemodialysis alone or followed by continuous renal replacement therapy.Results Dabigatran concentrations decreased by 52%-77% during intermittent hemodialysis but rebounded up to 87% within 2 hours after completion of dialysis. Initiation of continuous renal replacement therapy after intermittent hemodialysis attenuated the rebound effect in one patient and contributed to a reduction in dabigatran concentrations of 81% over 30 hours.Conclusions Extracorporeal therapy lowered dabigatran concentrations, suggesting that it removed the drug and may effectively accelerate total clearance, especially in patients with impaired kidney function. The use of prolonged intermittent hemodialysis or intermittent hemodialysis followed by continuous renal replacement therapy is recommended for the management of life-threatening bleeding in patients receiving dabigatran. The advantage of extracorporeal therapy should be weighed against the risk of bleeding with catheter insertion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Extracorporeal Therapy for Dabigatran Removal in the Treatment of Acute Bleeding

Singh

Maw

Henry³

et al. 2013

Clinical Journal of the American Society of Nephrology

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“…The pharmacokinetics of dabigatran have been evaluated in several studies [23,30,39,[57][58][59][60][61][62][63]. In an open-label, parallel group study [39], subjects given one dose of dabigatran (150 mg) were stratified by severity of renal impairment (mild, creatinine clearance (CrCl) >50 to ≤80 mL/min; moderate, CrCl >30 to ≤50 mL/min; severe, CrCl ≤30 mL/min).…”

Section: Pharmacokinetics Of Dabigatran In Kidney Disease and Hemodiamentioning

confidence: 99%

Enhanced Elimination of Dabigatran Through Extracorporeal Methods

2014

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Several pharmacokinetic studies have suggested that dabigatran possesses a number of ideal properties for expedited removal via extracorporeal methods. However, this practice has not been prospectively evaluated in patients with life-threatening bleeding or requiring emergency surgery secondary to dabigatran-associated coagulopathy. The purpose of this literature review is to evaluate the published evidence surrounding extracorporeal removal of dabigatran in the setting of emergency surgery or life-threatening bleeding. A query of MEDLINE, Web of Science, International Pharmaceutical Abstracts, and Google Scholar using the terms dabigatran, dabigatran etexilate, hemodialysis, renal replacement therapy, hemorrhage, and atrial fibrillation was used to retrieve relevant literature. Furthermore, a manual search of the references of the identified literature was performed to capture additional data. Current evidence suggests that extracorporeal removal of dabigatran may play a role in the setting of life-threatening bleeding and emergent surgery. Conflicting evidence exists with regard to the potential for redistribution based on serum dabigatran concentrations. In addition, a number of practicalities must be considered before incorporating this technique in the clinical setting. Extracorporeal removal of dabigatran may be a treatment modality in selected patients who require emergency reversal.

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“…In patients with normal renal function, approximately 80% of an intravenous dabigatran dose is excreted in urine with an elimination half-life of 12-17 h [25]. Renal impairment increases the elimination half-life to 15-34 h [23,26].…”

Section: Pharmacokineticsmentioning

confidence: 99%

Dabigatran: Review of Pharmacology and Management of Bleeding Complications of This Novel Oral Anticoagulant

et al. 2011

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Dabigatran (Pradaxa) is a competitive direct thrombin inhibitor approved by the US FDA for prevention of embolic stroke in patients with nonvalvular atrial fibrillation. Dabigatran has a pharmacokinetic profile that produces predictable anticoagulation responses, does not undergo CYP 450 metabolism, has few drug-drug and drug-food interactions, and does not require frequent laboratory monitoring of clotting parameters. Clinicians are rapidly prescribing this agent as a replacement for warfarin therapy. However, no therapeutic agent has been accepted to reliably reverse the hemorrhagic complications of dabigatran. As of yet, there is no solid evidence to guide management of bleeding complications; management should start with local control of bleeding when possible and transfusion of pRBCs if needed. Transfusion of FFP would not be expected to help control bleeding. Limited and mixed data exist for transfusion of factor VIIa and prothrombin complex concentrates; these therapies should be considered as well as dialysis, which will increase elimination in patients with life-threatening or closed-space bleeding due to dabigatran. We present an article that reviews the pharmacokinetics, clinical trial literature, and consensus guidelines regarding this novel oral anticoagulant.

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Pharmacokinetics and Pharmacodynamics of the Direct Oral Thrombin Inhibitor Dabigatran in Healthy Elderly Subjects

Cited by 392 publications

References 3 publications

Extracorporeal Therapy for Dabigatran Removal in the Treatment of Acute Bleeding

Extracorporeal Therapy for Dabigatran Removal in the Treatment of Acute Bleeding

Enhanced Elimination of Dabigatran Through Extracorporeal Methods

Dabigatran: Review of Pharmacology and Management of Bleeding Complications of This Novel Oral Anticoagulant

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