The pharmacokinetics and pharmacodynamics of argatroban: Effects of age, gender, and hepatic or renal dysfunction

Study Objective. To determine the pharmacokinetics and pharmacodynamics of argatroban in healthy volunteers and patients with hepatic or renal dysfunc tion. 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 volu nteers with hepatic disease; study 3, volunteers with normal to severely im paired renal function assigned to one of four groups based on creatinine cl earance. Intervention. Study 1, argatroban 125-pg/kg bolus followed by 4-hour contin uous infusion of 2.5 mu g/kg/minute; study 2, 4-hour infusion of 2.5 mu g/k g/minute (1.25 mu g/kg/minute in one patient with hepatic impairment); stud y 3,5-mu g/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 (aP TT), and whole blood activated clotting time (ACT). Study 1: the pharmacoki netic profile was well described by a two-compartment model with first-orde r elimination; effect response and plasma argatroban concentrations were we ll 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 ef fect of age or gender was the approximately 20% lower clearance in elderly men versus elderly women, which did not translate to clinically or statisti cally significant differences in pharmacodynamic response. Study 2. in pati ents with hepatic impairment, area under the concentration versus time curv e (AUC) from time zero (t(0)) to last measurable concentration, AUC from to to infinity, maximum concentration, and half-life of argatroban were incre ased approximately 2- to 3-fold; clearance was one-fourth that of healthy v olunteers. 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 p otential for underdosing or overdosing, regardless of age, gender, or renal function. Dosing precautions are recommended, however, in patients with he patic dysfunction.