Comparison of Anticoagulant Effects
Comparison of Anticoagulant Effects
Study Objective: To evaluate and compare the relationship between dosage and coagulation parameters, as well as safety profiles, of ascending bolus and infusion dosages of argatroban versus heparin in three phase I studies.
Design: Two randomized, double-blind studies compared argatroban and heparin, and one open-label, dose-escalation study further evaluated argatroban.
Setting: University teaching hospital clinical research unit.
Patients: Healthy men (aged 22-62 yrs).
Intervention: In the first study, 36 subjects received an argatroban 30-, 60-, 120-, or 240-µg/kg bolus, or a heparin 30-, 60-, 120-, or 240-U/kg bolus for three subjects, then amended to 15, 30, 60, or 120 U/kg. In the second study, 37 subjects received argatroban 1.25, 2.5, 5, or 10 µg/kg/minute with or without a 250-µg/kg bolus, or heparin 0.15, 0.20, 0.25, or 0.30 U/kg/minute with or without a 125-U/kg bolus. In the third study (open-label), nine subjects received an argatroban 250-µg/kg bolus plus an infusion of 15, 20, 30, and 40 µg/kg/minute.
Measurements and Main Results: When administered as a bolus dose in the first study, argatroban and heparin both produced dose-related increases in activated clotting time (ACT) and activated partial thromboplastin time (aPTT) within 10 minutes of administration. Dissipation of anticoagulant effect was approximately 4-fold faster for argatroban than for heparin. When administered by infusion with or without a bolus in the second study, argatroban, but not heparin, produced predictable dose-related increases in ACT and aPTT that were generally consistent across both effect measures and modes of administration. Effect steady state was attained by five or more subjects per dosing group receiving argatroban (5-9) but typically two or fewer subjects per group receiving heparin (0-7). Furthermore, upon cessation of infusion, anticoagulant effects dissipated faster for argatroban (effect half-life 18-41 min) than for heparin (effect half-life 23-134 min). When argatroban was infused without a bolus, peak and effect steady-state values for ACT and aPTT generally were attained within 1-3 hours. Data from the second and third studies show that for argatroban dosages up to 40 µg/kg/minute, plasma drug concentrations attained at 4 hours of infusion increased linearly with dose, and weight-adjusted plasma clearance was dose independent. In all studies, argatroban and heparin were well tolerated.
Conclusion: Anticoagulation was more predictable with argatroban than with heparin as measured by ACT and aPTT, with comparable safety profiles.
Although it is difficult to dose heparin accurately because of widespread interpatient variability and unpredictable anticoagulant response, the drug is the most frequently prescribed anticoagulant with antithrombin activity. Its anticoagulant effect is routinely monitored by measuring activated partial thromboplastin time (aPTT) or whole-blood activated clotting time (ACT). Heparin's limitations are due primarily to its chemical heterogeneity, widespread binding to proteins and endothelial cells, and inability to affect thrombin-bound fibrin or surface-bound factor Xa. Heparin also is associated with several adverse events, including bleeding, heparin-induced thrombocytopenia (HIT), and HIT with thrombosis syndrome (HITTS). Although the frequencies of HIT (up to 4%) and HITTS (~1%) are relatively low, these adverse events remain major concerns.
Owing to the inherent difficulties with heparin, new agents have been developed as alternatives for anticoagulation, such as the antithrombin agents. Thrombin was a target for drug development because as an enzyme in the coagulation cascade, it converts fibrinogen to fibrin, induces platelet aggregation, and activates coagulation factors V, VIII, and XIII, as well as proteins C and S. Argatroban is a nonheparin, small-molecule (anhydrous molecular weight 509), synthetic arginine derivative that effectively inhibits thrombin. It is a combination of 21-(R) and 21-(S) diastereoisomers that exist as an approximate 64:36 mixture (~2:1 ratio). The 21-(S) isomer has twice as much potency as the 21-(R) isomer with regard to thrombin inhibition. Argatroban undergoes hepatic metabolism by hydroxylation and aromatization in healthy humans, with 22.8% of unchanged drug excreted in urine within 24 hours of the end of infusion.
Thrombus formation is inhibited by argatroban in various animal models. In Japan, argatroban is approved for use in peripheral arterial occlusive disease, acute cerebral thrombosis, and hemodialysis in patients with antithrombin III deficiency, and is being evaluated as an anticoagulant in a variety of other conditions. In early Japanese clinical trials, however, the agent's efficacy and safety profiles are difficult to evaluate fully. Argatroban is under investigation as anticoagulant therapy in patients with HIT or HITTS.
The aPTT commonly is measured to monitor heparin therapy; when heparin concentrations are above 1 U/ml, aPTT no longer may be quantifiable and ACT can be measured. There are difficulties, however, with these monitoring tests, such as lack of a standard assay and numerous biologic factors that may alter values. Alternative methods have been investigated, although clinical trials are necessary to determine their cost-effectiveness and clinical efficacy, and easily performed assays are necessary for more effective measures. In addition, although a more appropriate pharmacodynamic index of efficacy for heparin may be successful prophy-laxis of thrombosis, this effect is not measurable in a healthy population. Consequently, surrogate parameters of the effects of heparin on the coagulation cascade (aPTT, ACT) are used. Currently, aPTT and ACT remain the most common measures for monitoring heparin therapy and were used in phase I comparative studies of heparin and argatroban, especially since measuring end points such as recurrent thromboembolism, death, or myocardial infarction is not feasible in healthy subjects.
No United States studies reported to date systematically evaluated bolus argatroban doses or directly compared argatroban with heparin in healthy volunteers. The primary objectives of three phase I studies were to evaluate and compare the safety profiles, as well as the relationships between dosage and coagulation parameters, of ascending bolus and infusion dosages of argatroban and heparin in healthy volunteers.
Study Objective: To evaluate and compare the relationship between dosage and coagulation parameters, as well as safety profiles, of ascending bolus and infusion dosages of argatroban versus heparin in three phase I studies.
Design: Two randomized, double-blind studies compared argatroban and heparin, and one open-label, dose-escalation study further evaluated argatroban.
Setting: University teaching hospital clinical research unit.
Patients: Healthy men (aged 22-62 yrs).
Intervention: In the first study, 36 subjects received an argatroban 30-, 60-, 120-, or 240-µg/kg bolus, or a heparin 30-, 60-, 120-, or 240-U/kg bolus for three subjects, then amended to 15, 30, 60, or 120 U/kg. In the second study, 37 subjects received argatroban 1.25, 2.5, 5, or 10 µg/kg/minute with or without a 250-µg/kg bolus, or heparin 0.15, 0.20, 0.25, or 0.30 U/kg/minute with or without a 125-U/kg bolus. In the third study (open-label), nine subjects received an argatroban 250-µg/kg bolus plus an infusion of 15, 20, 30, and 40 µg/kg/minute.
Measurements and Main Results: When administered as a bolus dose in the first study, argatroban and heparin both produced dose-related increases in activated clotting time (ACT) and activated partial thromboplastin time (aPTT) within 10 minutes of administration. Dissipation of anticoagulant effect was approximately 4-fold faster for argatroban than for heparin. When administered by infusion with or without a bolus in the second study, argatroban, but not heparin, produced predictable dose-related increases in ACT and aPTT that were generally consistent across both effect measures and modes of administration. Effect steady state was attained by five or more subjects per dosing group receiving argatroban (5-9) but typically two or fewer subjects per group receiving heparin (0-7). Furthermore, upon cessation of infusion, anticoagulant effects dissipated faster for argatroban (effect half-life 18-41 min) than for heparin (effect half-life 23-134 min). When argatroban was infused without a bolus, peak and effect steady-state values for ACT and aPTT generally were attained within 1-3 hours. Data from the second and third studies show that for argatroban dosages up to 40 µg/kg/minute, plasma drug concentrations attained at 4 hours of infusion increased linearly with dose, and weight-adjusted plasma clearance was dose independent. In all studies, argatroban and heparin were well tolerated.
Conclusion: Anticoagulation was more predictable with argatroban than with heparin as measured by ACT and aPTT, with comparable safety profiles.
Although it is difficult to dose heparin accurately because of widespread interpatient variability and unpredictable anticoagulant response, the drug is the most frequently prescribed anticoagulant with antithrombin activity. Its anticoagulant effect is routinely monitored by measuring activated partial thromboplastin time (aPTT) or whole-blood activated clotting time (ACT). Heparin's limitations are due primarily to its chemical heterogeneity, widespread binding to proteins and endothelial cells, and inability to affect thrombin-bound fibrin or surface-bound factor Xa. Heparin also is associated with several adverse events, including bleeding, heparin-induced thrombocytopenia (HIT), and HIT with thrombosis syndrome (HITTS). Although the frequencies of HIT (up to 4%) and HITTS (~1%) are relatively low, these adverse events remain major concerns.
Owing to the inherent difficulties with heparin, new agents have been developed as alternatives for anticoagulation, such as the antithrombin agents. Thrombin was a target for drug development because as an enzyme in the coagulation cascade, it converts fibrinogen to fibrin, induces platelet aggregation, and activates coagulation factors V, VIII, and XIII, as well as proteins C and S. Argatroban is a nonheparin, small-molecule (anhydrous molecular weight 509), synthetic arginine derivative that effectively inhibits thrombin. It is a combination of 21-(R) and 21-(S) diastereoisomers that exist as an approximate 64:36 mixture (~2:1 ratio). The 21-(S) isomer has twice as much potency as the 21-(R) isomer with regard to thrombin inhibition. Argatroban undergoes hepatic metabolism by hydroxylation and aromatization in healthy humans, with 22.8% of unchanged drug excreted in urine within 24 hours of the end of infusion.
Thrombus formation is inhibited by argatroban in various animal models. In Japan, argatroban is approved for use in peripheral arterial occlusive disease, acute cerebral thrombosis, and hemodialysis in patients with antithrombin III deficiency, and is being evaluated as an anticoagulant in a variety of other conditions. In early Japanese clinical trials, however, the agent's efficacy and safety profiles are difficult to evaluate fully. Argatroban is under investigation as anticoagulant therapy in patients with HIT or HITTS.
The aPTT commonly is measured to monitor heparin therapy; when heparin concentrations are above 1 U/ml, aPTT no longer may be quantifiable and ACT can be measured. There are difficulties, however, with these monitoring tests, such as lack of a standard assay and numerous biologic factors that may alter values. Alternative methods have been investigated, although clinical trials are necessary to determine their cost-effectiveness and clinical efficacy, and easily performed assays are necessary for more effective measures. In addition, although a more appropriate pharmacodynamic index of efficacy for heparin may be successful prophy-laxis of thrombosis, this effect is not measurable in a healthy population. Consequently, surrogate parameters of the effects of heparin on the coagulation cascade (aPTT, ACT) are used. Currently, aPTT and ACT remain the most common measures for monitoring heparin therapy and were used in phase I comparative studies of heparin and argatroban, especially since measuring end points such as recurrent thromboembolism, death, or myocardial infarction is not feasible in healthy subjects.
No United States studies reported to date systematically evaluated bolus argatroban doses or directly compared argatroban with heparin in healthy volunteers. The primary objectives of three phase I studies were to evaluate and compare the safety profiles, as well as the relationships between dosage and coagulation parameters, of ascending bolus and infusion dosages of argatroban and heparin in healthy volunteers.
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