ARGATROBAN (Page 5 of 6)

12.3 Pharmacokinetics


Argatroban distributes mainly in the extra cellular 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 α 1 – acid glycoprotein being 20% and 34%, respectively.


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%).


Argatroban is excreted primarily in the feces, presumably through biliary secretion. In a study in which 14 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.

Special Populations

Hepatic Impairment: The dosage of argatroban should be decreased in patients with hepatic impairment [ see Dosage and Administration (2.4) and Warnings and Precautions (5.2)]. 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).

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.

Use of argatroban was evaluated in a study of 12 patients with stable end-stage renal disease undergoing chronic intermittent hemodialysis. Argatroban was administered at a rate of 2 to 3 mcg/kg/min (begun at least 4 hours prior to dialysis) or as a bolus dose of 250 mcg/kg at the start of dialysis followed by a continuous infusion of 2 mcg/kg/min. Although these regimens did not achieve the goal of maintaining ACT values at 1.8 times the baseline value throughout most of the hemodialysis period, the hemodialysis sessions were successfully completed with both of these regimens. The mean ACTs produced in this study ranged from 1.39 to 1.82 times baseline, and the mean aPTTs ranged from 1.96 to 3.4 times baseline. When argatroban was administered as a continuous infusion of 2 mcg/kg/min prior to and during a 4-hour hemodialysis session, approximately 20% was cleared through dialysis.

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

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.

Aspirin and Acetaminophen: Drug-drug interactions have not been demonstrated between argatroban and concomitantly administered aspirin (162.5 mg orally given 26 and 2 hours prior to initiation of argatroban 1 mcg/kg/min over 4 hours) or acetaminophen (1,000 mg orally given 12, 6, and 0 hours prior to, and 6 and 12 hours subsequent to, initiation of argatroban 1.5 mcg/kg/min over 18 hours).


13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity studies with argatroban have not been performed.

Argatroban was not genotoxic in the Ames test, the Chinese hamster ovary cell (CHO/HGPRT) forward mutation test, the Chinese hamster lung fibroblast chromosome aberration test, the rat hepatocyte, and WI-38 human fetal lung cell unscheduled DNA synthesis (UDS) tests, or the mouse micronucleus test.

Argatroban at intravenous doses up to 27 mg/kg/day (0.3 times the recommended maximum human dose based on body surface area) had no effect on fertility and reproductive function of male and female rats.


14.1 Heparin-Induced Thrombocytopenia

The safety and efficacy of argatroban were evaluated in 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 had a clinical diagnosis of heparin-induced thrombocytopenia, either without thrombosis (HIT) or with thrombosis (HITTS [heparin-induced thrombocytopenia and thrombosis syndrome]) and were males or non-pregnant females between the ages 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 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 had documented histories of positive heparin-dependent antibody tests without current thrombocytopenia or heparin challenge (e.g., patients with latent disease) were also included if they required anticoagulation.

These studies did not include patients with documented unexplained aPTT > 200% of control at baseline, documented coagulation disorder or bleeding diathesis unrelated to HIT, a lumbar puncture within the past 7 days or a history of previous aneurysm, hemorrhagic stroke, or a thrombotic stroke within the past 6 months unrelated to HIT.

The initial dose of argatroban was 2 mcg/kg/min. Two hours after the start of the argatroban infusion, an aPTT level was obtained and dose adjustments were made (up to a maximum of 10 mcg/kg/min) to achieve a steady-state aPTT value that was 1.5 to 3 times the baseline value, not to exceed 100 seconds. Overall the mean aPTT level for HIT and HITTS patients during the Argatroban infusion increased from baseline values of 34 and 38 seconds, respectively, to 62.5 and 64.5 seconds, respectively.

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, a total of 304 patients were enrolled as follows: active HIT (n=129), active HITTS (n=144), or latent disease (n=31). 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.

There was 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 9). The components of the composite endpoint are shown in Table 9.

a) Death (all causes), amputation (all causes), or new thrombosis within 37-day study period.

b) Reported as the most severe outcome among the components of composite endpoint (severity ranking: death > amputation > new thrombosis); patients may have had multiple outcomes.

Table 9. Efficacy Results of Study 1: Composite Endpoint a and Individual Components, Ranked by Severity b
Parameter, N (%) Control n = 147 Argatroban n = 160 Control n = 46 Argatroban n = 144 Control n = 193 Argatroban n = 304
Composite Endpoint 57 (38.8) 41 (25.6) 26 (56.5) 63 (43.8) 83 (43) 104 (34.2)
Individual Components b:
Parameter, N (%) Control n = 147 Argatroban n = 160 Control n = 46 Argatroban n = 144 Control n = 193 Argatroban n = 304
Death Amputation New Thrombosis 32(21.8) 3(2) 22(15) 27(16.9) 3(1.9) 11(6.9) 13(28.3) 4(8.7) 9(19.6) 26(18.1) 16(11.1) 21(14.6) 45(23.3) 7(3.6) 31(16.1) 53(17.4) 19(6.2) 32(10.5)

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.

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.

Figure 3.
Time-to-First Event for the Composite Efficacy Endpoint: HIT Patients STUDY 1

Figure 3
(click image for full-size original)

Figure 4. Time-to-First Event for the Composite Efficacy Endpoint: HITTS Patients STUDY 1

Figure 4
(click image for full-size original)

In Study 2, a total of 264 patients were enrolled as follows: HIT (n=125) or HITTS (n=139). There was a 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% vs. 56.5%), and patients having either HIT or HITTS (33.7% vs. 43%). 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 ± 0.1 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, 53% of patients with HIT and 58% of patients 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.

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