The pharmacokinetics and pharmacodynamics of argatroban: effects of age, gender, and hepatic or renal dysfunction.
OBJECTIVE
To determine the pharmacokinetics and pharmacodynamics of argatroban in healthy volunteers and patients with hepatic or renal dysfunction.


METHODS
Prospective, open-label study (studies 1 and 3); prospective, open-label, parallel-group study (study 2).


METHODS
Two research centers and an inpatient clinic.


METHODS
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.


METHODS
Study 1, argatroban 125-microg/kg bolus followed by 4-hour continuous infusion of 2.5 microg/kg/minute; study 2, 4-hour infusion of 2.5 microg/kg/minute (1.25 microg/kg/minute in one patient with hepatic impairment); study 3, 5-microg/kg/minute continuous infusion over 4 hours.


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.


CONCLUSIONS
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.
Swan
S K
SK
Division of Nephrology, Hennepin County Medical Center and Total Renal Research, Inc., Minneapolis, Minnesota 55415, USA.
Hursting
M J
MJ
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019540:Area Under Curve; D001120:Arginine / Q000031:analogs & derivatives; D005260:Female; D006801:Humans; D007668:Kidney / Q000187:drug effects; D007674:Kidney Diseases / Q000378:metabolism / Q000503:physiopathology*; D008099:Liver / Q000187:drug effects; D008107:Liver Diseases / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D008910:Minnesota; D010875:Pipecolic Acids / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology*; D011446:Prospective Studies; D011792:Quebec; D012737:Sex Factors; D013449:Sulfonamides; D013781:Texas
D000925:Anticoagulants; D010875:Pipecolic Acids; D013449:Sulfonamides; D001120:Arginine; C031942:argatroban