Mechanism of Action: Argatroban is a direct thrombin inhibitor that reversibly binds to the thrombin active site. Argatroban does not require the co-factor antithrombin III for antithrombotic activity. Argatroban exerts its anticoagulant effects by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation; activation of coagulation factors V, VIII, and XIII; activation of protein C; and platelet aggregation.

Argatroban is highly selective for thrombin with an inhibitory constant (Ki) of 0.04 μM. At therapeutic concentrations, Argatroban has little or no effect on related serine proteases (trypsin, factor Xa, plasmin, and kallikrein).

Argatroban is capable of inhibiting the action of both free and clot-associated thrombin.

Argatroban does not interact with heparin-induced antibodies. Evaluation of sera in 12 healthy subjects and 8 patients who received multiple doses of Argatroban did not reveal antibody formation to Argatroban (see Clinical Studies).

Pharmacokinetics: Distribution: Argatroban distributes mainly in the extracellular fluid as evidenced by an apparent steady-state volume of distribution of 174 mL/kg (12.18 L in a 70-kg adult). Argatroban is 54% bound to human serum proteins, with binding to albumin and α1-acid glycoprotein being 20% and 34%, respectively.

Metabolism: The main route of Argatroban metabolism is hydroxylation and aromatization of the 3-methyltetrahydroquinoline ring in the liver. The formation of each of the 4 known metabolites is catalyzed in vitro by the human liver microsomal cytochrome P450 enzymes CYP3A4/5. The primary metabolite (M1) exerts 3- to 5-fold weaker anticoagulant effects than Argatroban. Unchanged Argatroban is the major component in plasma. The plasma concentrations of M1 range between 0% and 20% of that of the parent drug. The other metabolites (M2 to M4) are found only in very low quantities in the urine and have not been detected in plasma or feces. These data, together with the lack of effect of erythromycin (a potent CYP3A4/5 inhibitor) on Argatroban pharmacokinetics, suggest that CYP3A4/5-mediated metabolism is not an important elimination pathway in vivo.

Total body clearance is approximately 5.1 mL/kg/min (0.31 L/kg/hr) for infusion doses up to 40 mcg/kg/min. The terminal elimination half-life of Argatroban ranges between 39 and 51 minutes.

There is no interconversion of the 21-(R):21-(S) diastereoisomers. The plasma ratio of these diastereoisomers is unchanged by metabolism or hepatic impairment, remaining constant at 65:35 (±2%).

Excretion: Argatroban is excreted primarily in the feces, presumably through biliary secretion. In a study in which 14C-Argatroban (5 mcg/kg/min) was infused for 4 hours into healthy subjects, approximately 65% of the radioactivity was recovered in the feces within 6 days of the start of infusion with little or no radioactivity subsequently detected. Approximately 22% of the radioactivity appeared in the urine within 12 hours of the start of infusion. Little or no additional urinary radioactivity was subsequently detected. Average percent recovery of unchanged drug, relative to total dose, was 16% in urine and at least 14% in feces.

Pharmacokinetic/Pharmacodynamic Relationship: When Argatroban is administered by continuous infusion, anticoagulant effects and plasma concentrations of Argatroban follow similar, predictable temporal response profiles, with low intersubject variability. Immediately upon initiation of Argatroban infusion, anticoagulant effects are produced as plasma Argatroban concentrations begin to rise. Steady-state levels of both drug and anticoagulant effect are typically attained within 1 to 3 hours and are maintained until the infusion is discontinued or the dosage adjusted. Steady-state plasma Argatroban concentrations increase proportionally with dose (for infusion doses up to 40 mcg/kg/min

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