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OVERVIEW OF INTRAVENOUS DIRECT THROMBIN INHIBITORS

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Intravenous (IV) direct thrombin inhibitors (DTIs), including argatroban, bivalirudin, and lepirudin have been developed and evaluated for the treatment of heparin-induced thrombocytopenia (HIT), acute coronary syndrome (ACS), percutaneous coronary intervention (PCI), and venous thromboembolism (VTE). DTIs exert their anticoagulant effect by binding directly to thrombin, thereby inhibiting both soluble and fibrin-bound thrombin.1 The direct binding to thrombin produces an anticoagulant effect independent of antithrombin (AT) activity. The ability to bind to fibrin-bound thrombin may be particularly advantageous in the setting of an active clot, such as a coronary thrombosis, because fibrin-bound thrombin can stimulate further clotting activity. In addition, compared to heparin-based regimens, DTIs may offer a more predictable anticoagulant effect due to their lack of binding to other plasma proteins. Furthermore, DTIs are a mainstay therapy in patients with HIT because they are not associated with immune-mediated thrombocytopenia.

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DTIs were developed after the discovery of hirudin, a peptide first isolated from the salivary glands of medicinal leeches.2,3 Currently, three IV DTIs are approved for use in North America: argatroban, bivalirudin, and lepirudin. However, as of May 31, 2012, the manufacturer of lepirudin discontinued production and distribution of lepirudin.4 At the time of writing this chapter, no other manufacturers were producing lepirudin; therefore, its current use in practice is limited and will likely cease once supply is exhausted.

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PHARMACOKINETICS

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ARGATROBAN

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Argatroban is a small (molecular weight 500 kDa) synthetic DTI administered as a continuous IV infusion due to its limited bioavailability if administered orally.5 Upon initiation of an infusion, anticoagulant effect is seen immediately. The volume of distribution is approximately 174–180 mL/kg, with protein binding observed at 20 percent and 35 percent to albumin and alpha-1-acid glycoprotein, respectively. Argatroban is hepatically cleared primarily via hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring. Minor metabolism to four known metabolites through cytochrome (CYP)-450 3A4/5 has been observed. Plasma concentration of metabolite M1 is 0–20 percent parent drug concentration, and this metabolite has a pharmacodynamics effect three–five times weaker than argatroban. Metabolites M2 to M4 are found in low quantities and are pharmacodynamically inactive. Total clearance ranges from 4.7 to 5.1 mL/kg/min at doses up to 40 mcg/kg/min, but such clearance is reduced to 1.9 mL/kg/min in hepatic impairment. The elimination half-life of argatroban is approximately 39–51 minutes but extends to 181 minutes in patients with hepatic dysfunction (defined as Child-Pugh score >6). Therefore, dose adjustment and close monitoring in patients with hepatic impairment are essential. Approximately 20 percent of argatroban is removed through hemodialysis.

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BIVALIRUDIN

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Bivalirudin is a 20-amino-acid semisynthetic polypeptide analog of hirudin administered as a continuous IV infusion.6 Although not usually administered subcutaneously, the bioavailability of bivalirudin is approximately 40 percent when given in this manner. When administered as an IV infusion, bivalirudin is also relatively rapid acting with anticoagulant ...

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