The Pharmacokinetics and Pharmacodynamics of Argatroban...
Study Objective: To determine the pharmacokinetics and pharmacodynamics of argatroban in healthy volunteers and patients with hepatic or renal dysfunction.
Design: Prospective, open-label study (studies 1 and 3); prospective, open-label, parallel-group study (study 2).
Settings: Two research centers and an inpatient clinic.
Subjects: Study 1, healthy volunteers; study 2, healthy volunteers and volunteers with hepatic disease; study 3, volunteers with normal to severely impaired renal function assigned to one of four groups based on creatinine clearance.
Intervention: Study 1, argatroban 125-µg/kg bolus followed by 4-hour continuous infusion of 2.5 µg/kg/minute; study 2, 4-hour infusion of 2.5 µg/kg/minute (1.25 µg/kg/minute in one patient with hepatic impairment); study 3, 5-µg/kg/minute continuous infusion over 4 hours.
Measurements and Main Results. Blood samples were obtained to assess plasma argatroban concentration, plasma activated partial thromboplastin time (aPTT), and whole blood activated clotting time (ACT). Study 1: the pharmacokinetic profile was well described by a two-compartment model with first-order elimination; effect response and plasma argatroban concentrations were well correlated. Mean ± SD clearance, steady-state volume of distribution, and half-life values (40 healthy volunteers) were 4.7 ± 1.1 ml/minute/kg, 179.5 ± 33.0 ml/kg, and 46.2 ± 10.2 minutes, respectively. The only effect of age or gender was the approximately 20% lower clearance in elderly men versus elderly women, which did not translate to clinically or statistically significant differences in pharmacodynamic response. Study 2: in patients with hepatic impairment, area under the concentration versus time curve (AUC) from time zero (t0) to last measurable concentration, AUC from t0 to infinity, maximum concentration, and half-life of argatroban were increased approximately 2- to 3-fold; clearance was one-fourth that of healthy volunteers. For aPTT and ACT, AUC over time for mean effect and mean maximum effect was higher in these volunteers. Study 3: no significant differences were detected. All four groups had predictable response profiles over time.
Conclusion. Argatroban should be easy to monitor and control, with little potential for underdosing or overdosing, regardless of age, gender, or renal function. Dosing precautions are recommended, however, in patients with hepatic dysfunction.
Argatroban (Novastan; Texas Biotechnology Corporation, Houston, TX; SmithKline Beecham Pharmaceuticals, Philadelphia, PA), a small-molecule, synthetic thrombin inhibitor derived from L-arginine, reversibly binds to the catalytic site region of thrombin. In contrast to the indirect thrombin inhibitor heparin, argatroban directly inhibits thrombin and does not require the cofactor antithrombin III for antithrombotic activity. It exerts its pharmacologic actions by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation and activation of coagulation factors V, VIII, and XIII, and the natural anticoagulant protein C. The agent is under investigation for therapy in patients with heparin-induced thrombocytopenia (HIT) or HIT with thrombosis syndrome (HITTS) who require anticoagulation.
A historically controlled trial (data on file, Texas Biotechnology Corp., Houston, TX) evaluated the efficacy and safety of argatroban 2 µg/kg/minute and adjusted to maintain plasma activated partial thromboplastin time (aPTT) 1.5-3.0 times the baseline value in 304 patients with HIT or HITTS. In addition, higher dosages were given to patients with HIT or HITTS during coronary procedures.
Factors that can influence the pharmaco-kinetics or pharmacodynamics of a drug include age, gender, renal dysfunction, and hepatic dysfunction. Optimization of dosing recommen-dations requires an understanding of their potential effects. Another direct thrombin inhibitor, recombinant hirudin, is predominantly renally excreted. Although published data regarding recombinant hirudin in renally impaired patients are limited, one study showed that its pharmacokinetic profile is markedly altered in hemodialyzed patients. A second form of recombinant hirudin was reported to have a total and renal clearance proportional to creatinine clearance (Clcr), with delayed elimination in patients with moderate to severe renal impairment. Accordingly, the agent requires diligent monitoring to prevent bleeding from supratherapeutic concentrations in such patients, especially those with severe renal impairment. In contrast, argatroban is hepatically metabolized, mainly by hydroxylation and aromatization of the 3-methyltetrahydro-quinolone ring. On the basis of in vitro studies, argatroban appears to be metabolized by cytochrome P450 (CYP) 3A4/5 enzymes; however, erythromycin does not appear to affect its pharmacokinetics. Therefore, in vivo CYP3A4/5-mediated oxidative metabolism does not appear to be an important elimination pathway for argatroban.
The purpose of this study was to provide data on the effects of age, gender, and renal or hepatic dysfunction on the pharmacokinetics and pharmacodynamics of argatroban. In three separate trials the pharmacokinetics and pharmacodynamics of this agent were evaluated in a total of 58 healthy men and women between ages 19 and 79, 18 patients with renal disease, and 5 patients with hepatic disease.
Study Objective: To determine the pharmacokinetics and pharmacodynamics of argatroban in healthy volunteers and patients with hepatic or renal dysfunction.
Design: Prospective, open-label study (studies 1 and 3); prospective, open-label, parallel-group study (study 2).
Settings: Two research centers and an inpatient clinic.
Subjects: Study 1, healthy volunteers; study 2, healthy volunteers and volunteers with hepatic disease; study 3, volunteers with normal to severely impaired renal function assigned to one of four groups based on creatinine clearance.
Intervention: Study 1, argatroban 125-µg/kg bolus followed by 4-hour continuous infusion of 2.5 µg/kg/minute; study 2, 4-hour infusion of 2.5 µg/kg/minute (1.25 µg/kg/minute in one patient with hepatic impairment); study 3, 5-µg/kg/minute continuous infusion over 4 hours.
Measurements and Main Results. Blood samples were obtained to assess plasma argatroban concentration, plasma activated partial thromboplastin time (aPTT), and whole blood activated clotting time (ACT). Study 1: the pharmacokinetic profile was well described by a two-compartment model with first-order elimination; effect response and plasma argatroban concentrations were well correlated. Mean ± SD clearance, steady-state volume of distribution, and half-life values (40 healthy volunteers) were 4.7 ± 1.1 ml/minute/kg, 179.5 ± 33.0 ml/kg, and 46.2 ± 10.2 minutes, respectively. The only effect of age or gender was the approximately 20% lower clearance in elderly men versus elderly women, which did not translate to clinically or statistically significant differences in pharmacodynamic response. Study 2: in patients with hepatic impairment, area under the concentration versus time curve (AUC) from time zero (t0) to last measurable concentration, AUC from t0 to infinity, maximum concentration, and half-life of argatroban were increased approximately 2- to 3-fold; clearance was one-fourth that of healthy volunteers. For aPTT and ACT, AUC over time for mean effect and mean maximum effect was higher in these volunteers. Study 3: no significant differences were detected. All four groups had predictable response profiles over time.
Conclusion. Argatroban should be easy to monitor and control, with little potential for underdosing or overdosing, regardless of age, gender, or renal function. Dosing precautions are recommended, however, in patients with hepatic dysfunction.
Argatroban (Novastan; Texas Biotechnology Corporation, Houston, TX; SmithKline Beecham Pharmaceuticals, Philadelphia, PA), a small-molecule, synthetic thrombin inhibitor derived from L-arginine, reversibly binds to the catalytic site region of thrombin. In contrast to the indirect thrombin inhibitor heparin, argatroban directly inhibits thrombin and does not require the cofactor antithrombin III for antithrombotic activity. It exerts its pharmacologic actions by inhibiting thrombin-catalyzed or -induced reactions, including fibrin formation and activation of coagulation factors V, VIII, and XIII, and the natural anticoagulant protein C. The agent is under investigation for therapy in patients with heparin-induced thrombocytopenia (HIT) or HIT with thrombosis syndrome (HITTS) who require anticoagulation.
A historically controlled trial (data on file, Texas Biotechnology Corp., Houston, TX) evaluated the efficacy and safety of argatroban 2 µg/kg/minute and adjusted to maintain plasma activated partial thromboplastin time (aPTT) 1.5-3.0 times the baseline value in 304 patients with HIT or HITTS. In addition, higher dosages were given to patients with HIT or HITTS during coronary procedures.
Factors that can influence the pharmaco-kinetics or pharmacodynamics of a drug include age, gender, renal dysfunction, and hepatic dysfunction. Optimization of dosing recommen-dations requires an understanding of their potential effects. Another direct thrombin inhibitor, recombinant hirudin, is predominantly renally excreted. Although published data regarding recombinant hirudin in renally impaired patients are limited, one study showed that its pharmacokinetic profile is markedly altered in hemodialyzed patients. A second form of recombinant hirudin was reported to have a total and renal clearance proportional to creatinine clearance (Clcr), with delayed elimination in patients with moderate to severe renal impairment. Accordingly, the agent requires diligent monitoring to prevent bleeding from supratherapeutic concentrations in such patients, especially those with severe renal impairment. In contrast, argatroban is hepatically metabolized, mainly by hydroxylation and aromatization of the 3-methyltetrahydro-quinolone ring. On the basis of in vitro studies, argatroban appears to be metabolized by cytochrome P450 (CYP) 3A4/5 enzymes; however, erythromycin does not appear to affect its pharmacokinetics. Therefore, in vivo CYP3A4/5-mediated oxidative metabolism does not appear to be an important elimination pathway for argatroban.
The purpose of this study was to provide data on the effects of age, gender, and renal or hepatic dysfunction on the pharmacokinetics and pharmacodynamics of argatroban. In three separate trials the pharmacokinetics and pharmacodynamics of this agent were evaluated in a total of 58 healthy men and women between ages 19 and 79, 18 patients with renal disease, and 5 patients with hepatic disease.