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Argatroban (Argatroban) - Description and Clinical Pharmacology



Argatroban is a synthetic direct thrombin inhibitor derived from L-arginine. The chemical name for Argatroban is 1-[5-[(aminoiminomethyl)amino]-1-oxo-2-[[(1,2,3,4-tetrahydro-3-methyl- 8-quinolinyl)sulfonyl]amino]pentyl]-4-methyl-2-piperidinecarboxylic acid, monohydrate. Argatroban has 4 asymmetric carbons. One of the asymmetric carbons has an R configuration (stereoisomer Type I) and an S configuration (stereoisomer Type II). Argatroban consists of a mixture of R and S stereoisomers at a ratio of approximately 65:35.

The molecular formula of Argatroban is C23H36N6O5S·H2O. Its molecular weight is 526.66.

Argatroban is a white, odorless crystalline powder that is freely soluble in glacial acetic acid, slightly soluble in ethanol, and insoluble in acetone, ethyl acetate, and ether. Argatroban Injection is a sterile clear, colorless to pale yellow, slightly viscous solution. Argatroban is available in 250-mg (in 2.5-mL) single-use amber vials, with gray flip-top caps. Each mL of sterile, nonpyrogenic solution contains 100 mg Argatroban. Inert ingredients: 750 mg D-sorbitol, 1,000 mg dehydrated alcohol.


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 (alpha)1-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 which14 C-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 in healthy subjects) and are well correlated with steady-state anticoagulant effects. For infusion doses up to 40 mcg/kg/min, Argatroban increases in a dose-dependent fashion, the activated partial thromboplastin time (aPTT), the activated clotting time (ACT), the prothrombin time (PT), the International Normalized Ratio (INR), and the thrombin time (TT) in healthy volunteers and cardiac patients. Representative steady-state plasma Argatroban concentrations and anticoagulant effects are shown below for Argatroban infusion doses up to 10 mcg/kg/min (see Figure 1).

Effect on International Normalized Ratio (INR): Because Argatroban is a direct thrombin inhibitor, co-administration of Argatroban and warfarin produces a combined effect on the laboratory measurement of the INR. However, concurrent therapy, compared to warfarin monotherapy, exerts no additional effect on vitamin K-dependent factor Xa activity.

The relationship between INR on co-therapy and warfarin alone is dependent on both the dose of Argatroban and the thromboplastin reagent used. This relationship is influenced by the International Sensitivity Index (ISI) of the thromboplastin. Data for 2 commonly utilized thromboplastins with ISI values of 0.88 (Innovin, Dade) and 1.78 (Thromboplastin C Plus, Dade) are presented in Figure 2 for an Argatroban dose of 2 mcg/kg/min. Thromboplastins with higher ISI values than shown result in higher INRs on combined therapy of warfarin and Argatroban. These data are based on results obtained in normal individuals (see PRECAUTIONS, Drug Interactions and DOSAGE AND ADMINISTRATION, Conversion to Oral Anticoagulant Therapy).

Figure 2 demonstrates the relationship between INR for warfarin alone and INR for warfarin co-administered with Argatroban at a dose of 2 mcg/kg/min. To calculate INR for warfarin alone (INRW), based on INR for co-therapy of warfarin and Argatroban (INRWA), when the Argatroban dose is 2 mcg/kg/min, use the equation next to the appropriate curve. Example: At a dose of 2 mcg/kg/min and an INR performed with Thromboplastin A, the equation 0.19 + 0.57 (INRWA) = INRW would allow a prediction of the INR on warfarin alone (INRW). Thus, using an INRWA value of 4.0 obtained on combined therapy: INRW= 0.19 + 0.57 (4) = 2.47 as the value for INR on warfarin alone. The error (confidence interval) associated with a prediction is ± 0.4 units. Similar linear relationships and prediction errors exist for Argatroban at a dose of 1 mcg/kg/min. Thus, for Argatroban doses of 1 or 2 mcg/kg/min, INRW can be predicted from INRWA. For Argatroban doses greater than 2 mcg/kg/min, the error associated with predicting INRW from INRWA is ±1. Thus, INRW cannot be reliably predicted from INRWA at doses greater than 2 mcg/kg/min.


Renal Impairment: No dosage adjustment is necessary in patients with renal dysfunction. The effect of renal disease on the pharmacokinetics of Argatroban was studied in 6 subjects with normal renal function (mean Clcr = 95 ± 16 mL/min) and in 18 subjects with mild (mean Clcr = 64 ± 10 mL/min), moderate (mean Clcr = 41 ± 5.8 mL/min), and severe (mean Clcr = 5 ± 7 mL/min) renal impairment. The pharmacokinetics and pharmacodynamics of Argatroban at dosages up to 5 mcg/kg/min were not significantly affected by renal dysfunction.

Hepatic Impairment: The dosage of Argatroban should be decreased in patients with hepatic impairment (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Patients with hepatic impairment were not studied in percutaneous coronary intervention (PCI) trials. At a dose of 2.5 mcg/kg/min, hepatic impairment is associated with decreased clearance and increased elimination half-life of Argatroban (to 1.9 mL/kg/min and 181 minutes, respectively, for patients with a Child-Pugh score >6).

Age, Gender: There are no clinically significant effects of age or gender on the pharmacokinetics or pharmacodynamics (e.g., aPTT) of Argatroban.

Drug-Drug Interactions: Digoxin: In 12 healthy volunteers, intravenous infusion of Argatroban (2 mcg/kg/min) over 5 days (study days 11 to 15) did not affect the steady-state pharmacokinetics of oral digoxin (0.375 mg daily for 15 days).

Erythromycin: In 10 healthy subjects, orally administered erythromycin (a potent inhibitor of CYP3A4/5) at 500 mg four times daily for 7 days had no effect on the pharmacokinetics of Argatroban at a dose of 1 mcg/kg/min for 5 hours. These data suggest oxidative metabolism by CYP3A4/5 is not an important elimination pathway in vivo for Argatroban.


Heparin-Induced Thrombocytopenia: Heparin-induced thrombocytopenia (HIT) is a potentially serious, immune-mediated complication of heparin therapy that is strongly associated with subsequent venous and arterial thrombosis. Whereas initial treatment of HIT is to discontinue administration of all heparin, patients may require anticoagulation for prevention and treatment of thromboembolic events.

The conclusion that Argatroban is an effective treatment for heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia and thrombosis syndrome (HITTS) is based upon the data from an historically controlled efficacy and safety study (Study 1) and a follow-on efficacy and safety study (Study 2). These studies were comparable with regard to study design, study objectives, dosing regimens as well as study outline, conduct, and monitoring.

In these studies, 568 adult patients were treated with Argatroban and 193 adult patients made up the historical control group. Patients were required to have a clinical diagnosis of heparin-induced thrombocytopenia, either without thrombosis (HIT) or with thrombosis (HITTS) and be males or non-pregnant females between the age of 18 and 80 years old. HIT/HITTS was defined by a fall in platelet count to less than 100,000/µL or a 50% decrease in platelets after the initiation of heparin therapy with no apparent explanation other than HIT. Patients with HITTS also had presence of an arterial or venous thrombosis documented by appropriate imaging techniques or supported by clinical evidence such as acute myocardial infarction, stroke, pulmonary embolism, or other clinical indications of vascular occlusion. Patients who required anticoagulation with documented histories of positive HIT antibody test were also eligible in the absence of thrombocytopenia or heparin challenge (e.g., patients with latent disease).

Patients with documented unexplained aPTT >200% of control at baseline, documented coagulation disorder or bleeding diathesis unrelated to HITTS, a lumbar puncture within the past 7 days or a history of previous aneurysm, hemorrhagic stroke, or recent thrombotic stroke, within the past 6 months, unrelated to HITTS were excluded from these studies.

The initial dose of Argatroban was 2 mcg/kg/min, not to exceed 10 mcg/kg/min. Two hours after the start of the Argatroban infusion, an aPTT level was obtained and dose adjustments were made to achieve a steady-state aPTT value that was 1.5 to 3.0 times the baseline value, not to exceed 100 seconds. In Study 1, the mean aPTT level for HIT patients was 38 seconds prior to start of Argatroban infusion. At first assessment, * during the Argatroban infusion, mean aPTT level for HIT patients was 64 seconds. Overall the mean aPTT level during the Argatroban infusion for HIT patients was 62.5 seconds. In Study 1, the mean aPTT level for HITTS patients was 34 seconds prior to start of Argatroban infusion. At first assessment, * during the Argatroban infusion, mean aPTT level for HITTS patients was 70 seconds. Overall, the mean aPTT level during the Argatroban infusion for HITTS patients was 64.5 seconds (see DOSAGE AND ADMINISTRATION).

(*First assessment was defined as occurring at least 2 hours post-infusion start time.)

The primary efficacy analysis was based on a comparison of event rates for a composite endpoint that included death (all causes), amputation (all causes) or new thrombosis during the treatment and follow-up period (study days 0 to 37). Secondary analyses included evaluation of the event rates for the components of the composite endpoint as well as time-to-event analyses.

In Study 1, 304 patients were enrolled having active HIT (129/304, 42%), active HITTS (144/304, 47%), or latent disease (31/304, 10%). Among the 193 historical controls, 139 (72%) had active HIT, 46 (24%) had active HITTS, and 8 (4%) had latent disease. Within each group, those with active HIT and those with latent disease were analyzed together. Positive laboratory confirmation of HIT/HITTS by the heparin-induced platelet aggregation test or serotonin release assay was demonstrated in 174 of 304 (57%) Argatroban-treated patients (i.e., in 80 with HIT or latent disease and 94 with HITTS) and in 149 of 193 (77%) historical controls (i.e., in 119 with HIT or latent disease and 30 with HITTS). The test results for the remainder of the patients and controls were either negative or not determined.

A categorical analysis showed a significant improvement in the composite outcome in patients with HIT and HITTS treated with Argatroban versus those in the historical control group (see Table 1). The components of the composite endpoint are shown in Table 2.

Table 1. Efficacy Results of Study 1: Composite Endpoint *
Parameter, N (%) Control n = 147 Argatroban n = 160 Control n = 46 Argatroban n = 144 Control n = 193 Argatroban n = 304
57 (38.8) 41 (25.6) 26 (56.5) 63 (43.8) 83 (43.0) 104 (34.2)
*Death (all causes), amputation (all causes), or new thrombosis within 37-day study period.

Table 2. Efficacy Results of Study 1: Components of the Composite Endpoint, Ranked by Severity *
Parameter, N (%) Control n = 147 Argatroban n = 160 Control n = 46 Argatroban n = 144 Control n = 193 Argatroban n = 304
Death 32 (21.8) 27 (16.9) 13 (28.3) 26 (18.1) 45 (23.3) 53 (17.4)
Amputation 3 (2.0) 3 (1.9) 4 (8.7) 16 (11.1) 7 (3.6) 19 (6.2)
New Thrombosis 22 (15.0) 11 (6.9) 9 (19.6) 21 (14.6) 31 (16.1) 32 (10.5)
*Reported as the most severe outcome among the components of composite endpoint (severity ranking: death > amputation > new thrombosis); patients may have had multiple outcomes.

Time-to-event analyses showed significant improvements in the time-to-first event in patients with HIT or HITTS treated with Argatroban versus those in the historical control group. The between-group differences in the proportion of patients who remained free of death, amputation, or new thrombosis were statistically significant in favor of Argatroban by these analyses (p = 0.007 in patients with HIT and p = 0.018 in patients with HITTS, according to log-rank test).

A time-to-event analysis for the composite endpoint is shown in Figure 3 for patients with HIT and Figure 4 for patients with HITTS.

*Censored indicates no clinical endpoint (defined as death, amputation, or new thrombosis) was observed during the follow-up period (maximum period of follow-up was 37 days).

*Censored indicates no clinical endpoint (defined as death, amputation, or new thrombosis) was observed during the follow-up period (maximum period of follow-up was 37 days).

In Study 2, 264 patients were enrolled, having either HIT (125/264, 47.3%) or HITTS (139/264, 52.7%), and then treated with Argatroban. Categorical analysis demonstrated significant improvement in the composite efficacy outcome for Argatroban-treated patients, versus the same historical control group from Study 1, among patients having HIT (25.6% vs. 38.8%), patients having HITTS (41.0% vs. 56.5%), and patients having either HIT or HITTS (33.7% vs. 43.0%). Time-to-event analyses showed significant improvements in the time-to-first event in patients with HIT or HITTS treated with Argatroban versus those in the historical control group. The between-group differences in the proportion of patients who remained free of death, amputation, or new thrombosis were statistically significant in favor of Argatroban.

Anticoagulant Effect: In Study 1, the mean (±SE) dose of Argatroban administered was 2.0 ± 0.1 mcg/kg/min in the HIT arm and 1.9 ± 0.1 mcg/kg/min in the HITTS arm. Seventy-six percent of patients with HIT and 81% of patients with HITTS achieved a target aPTT at least 1.5-fold greater than the baseline aPTT at the first assessment occurring on average at 4.6 hours (HIT) and 3.9 hours (HITTS) following initiation of Argatroban therapy.

No enhancement of aPTT response was observed in subjects receiving repeated administration of Argatroban.

Platelet Count Recovery: In Study 1, the majority of patients, 53% of those with HIT and 58% of those with HITTS, had a recovery of platelet count by day 3. Platelet Count Recovery was defined as an increase in platelet count to >100,000/µL or to at least 1.5-fold greater than the baseline count (platelet count at study initiation) by day 3 of the study.

Percutaneous Coronary Intervention (PCI) in HIT/HITTS Patients: In 3 similarly designed trials, Argatroban was administered to 91 patients with current or previous clinical diagnosis of HIT/HITTS or heparin-dependent antibodies, who underwent a total of 112 percutaneous coronary interventions (PCIs) including percutaneous transluminal coronary angioplasty (PTCA), coronary stent placement, or atherectomy.

Among the 91 patients undergoing their first PCI with Argatroban, notable ongoing or recent medical history included myocardial infarction (n = 35), unstable angina (n = 23), and chronic angina (n = 34). There were 33 females and 58 males. The average age was 67.6 years (median 70.7, range 44 to 86), and the average weight was 82.5 kg (median 81.0 kg, range 49 to 141).

Due to the history or presence of the heparin-dependent antibody or HIT/HITTS, these patients required alternative anticoagulation. Twenty-one of the 91 patients had a repeat PCI using Argatroban an average of 150 days after their initial PCI. Seven of 91 patients received glycoprotein IIb/IIIa inhibitors. Safety and efficacy were assessed against historical control populations.

Per protocol, all patients received oral aspirin (325 mg) 2 to 24 hours prior to the interventional procedure. After venous or arterial sheaths were in place, anticoagulation was initiated with a bolus of Argatroban of 350 mcg/kg via a large-bore IV line or through the venous sheath over 3 to 5 minutes. Simultaneously, a maintenance infusion of 25 mcg/kg/min was initiated to achieve a therapeutic activated clotting time (ACT) of 300 to 450 seconds. If necessary to achieve this therapeutic range, the maintenance infusion dose was titrated (15 to 40 mcg/kg/min) and/or an additional bolus dose of 150 mcg/kg could be given. Each patient's ACT was checked 5 to 10 minutes following the bolus dose. The ACT was checked as clinically indicated thereafter. Arterial and venous sheaths were removed no sooner than 2 hours after discontinuation of Argatroban and when the ACT was less than 160 seconds.

If a patient required anticoagulation after the procedure, Argatroban could be continued, but at a lower infusion dose between 2.5 and 5 mcg/kg/min. An aPTT was drawn 2 hours after this dose reduction and the dose of Argatroban then adjusted as clinically indicated (not to exceed 10 mcg/kg/min), to reach an aPTT between 1.5 and 3 times baseline value (not to exceed 100 seconds).

Ninety-one patients were treated with Argatroban on their first PCI, and 21 patients were reexposed to Argatroban on subsequent PCIs. In 92 of the 112 interventions (82%), the patient received the initial bolus of 350 mcg/kg and an initial infusion dose of 25 mcg/kg/min. The majority of patients did not require additional bolus dosing during the PCI procedure. The mean value for the initial ACT measurement after the start of dosing for all interventions was 379 sec (median 338 sec; 5th percentile-95th percentile 238 to 675 sec). The mean ACT value per intervention over all measurements taken during the procedure was 416 sec (median 390 sec; 5th percentile-95th percentile 261 to 698 sec). About 65% of patients had ACTs within the recommended range of 300 to 450 seconds throughout the procedure. The investigators did not achieve anticoagulation within the recommended range in about 23% of patients. However, in this small sample, patients with ACTs below 300 seconds did not have more coronary thrombotic events, and patients with ACTs over 450 seconds did not have higher bleeding rates.

Acute procedural success was defined as lack of death, emergent coronary artery bypass graft (CABG), or Q-wave myocardial infarction. Acute procedural success was reported in 98.2% of patients who underwent PCIs with Argatroban anticoagulation compared with 94.3% of historical control patients anticoagulated with heparin (p = NS). Among the 112 interventions, 2 patients had emergency CABGs, 3 had repeat PTCAs, 4 had non-Q-wave myocardial infarctions, 3 had myocardial ischemia, 1 had an abrupt closure, and 1 had an impending closure (some patients may have experienced more than 1 event). No patients died. Two patients had protocol-defined major bleeding, 1 of which was retroperitoneal and the other gastrointestinal. Minor bleeding, defined as spontaneous and observed with hemoglobin decreasing >3g/dL or with no bleeding site and hemoglobin decreasing >4g/dL, occurred in 4.5% of interventions.

Additional Information: Cardiac Therapy: The safety and effectiveness of Argatroban for cardiac indications outside of percutaneous coronary intervention in patients with HIT have not been established.

Reexposure and Lack of Antibody Formation: Plasma from 12 healthy volunteers treated with Argatroban over 6 days showed no evidence of neutralizing antibodies. Repeated administration of Argatroban to more than 40 patients was tolerated with no loss of anticoagulant activity. No change in the dose is required.

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