Pharmacological basis and clinical evidence of dabigatran therapy

Abstract

Dabigatran is an emerging oral anticoagulant which is a direct inhibitor of thrombin activity. It has been approved in the European Union and the United States of America for the prevention of thrombosis after major orthopedic surgery. It has also been approved by the American Food and Drug Administration and the European Medicines Agency for the prevention of stroke in chronic atrial fibrillation. Dabigatran provides a stable anticoagulation effect without any need to perform periodical laboratory controls. Of note, there is a growing amount of clinical evidence which shows its safety and efficacy. For these reasons, dabigatran may suppose a revolution in oral anticoagulation. However, two important limitations remain. First, it is contraindicated in patients with end-stage renal disease. Second, there is no evidence of the prevention of thrombosis in mechanical heart valves.

Pharmacogenetics of Novel Oral Anticoagulants: A Review of Identified Gene Variants & Future Perspectives

“…The results of this study imply that dabigatran is at least as efficient and safe as enoxaparin in prevention of VTE following total knee replacement [15]. Dabigatran is now approved for usage in both of these conditions by EMA and US FDA [10].…”

“…Dabigatran, delivered to patients in the form of dabigatran etexilate (DABE) that is rapidly hydrolyzed to dabigatran by P-glycoprotein (P-gp), is serving as a direct inhibitor of both free and clot-bound thrombin (factor II) activity. Thrombin activity is of the primary importance in human coagulation system as it activates fibrinogen (factor I), as well as factors V and XI of the coagulation system [9,10]. Dabigatran also inhibits conversion of fibrinogen to fibrin, a process carried out by thrombin as the last step in the coagulation cascade [9].…”

“…The drug is metabolized by plasmatic esterases, instead of interacting with cytochrome P450 [10]. Dabigatran peak plasma levels are reached within 2 h of ingestion, while drug half-life in adult patients is 14-17 h [9,11].…”

“…Due to 80% of digested drug being excreted in non-metabolized form via urine and 20% in metabolized form through stool, the drug is avoided in patients with impaired kidney function, and especially in patients with end-stage renal disease [10]. It has also been found that plasma concentrations of dabigatran tend be higher in women, elderly patients and those with body weight under 50 kg and over 100 kg [11].…”

Prevention and Treatment of Venous Thromboembolism and Pulmonary Embolism: The Role of Novel Oral Anticoagulants

“…It has a half-life elimination time of 14-17 hours in multiple dosing and 7-9 hours after single doses of 100-400 mg in healthy subjects [71] reaching its peak concentration in 1-2 hours after multiple administration of 150 mg [72]. Its maximum concentration in 150 mg BID administration is 146 ng/ml [73] and it has a predictable pharmacokinetic profile since its peak and area under curve (AUC) concentrations increase linearly with wide range dose variation of 10-200 mg/day [68]. Age does not seem to be related with plasma concentrations of dabigatran, despite the fact that the bioavailability of dabigatran was increased 1.7 to 2-fold in the elderly, probably due to descending renal function because of age [74].…”