Bivalirudin pharmacokinetics and pharmacodynamics: effect of renal function, dose, and gender.
BACKGROUND
These studies were conducted to determine whether bivalirudin clearance and pharmacodynamics are dependent on dose, renal function, or gender.


METHODS
Two studies were performed. The first comprised 25 patients who were undergoing percutaneous coronary intervention-8 with normal renal function, 11 with mild renal impairment, and 6 with moderate renal impairment. Each patient received a bolus dose of bivalirudin (1 mg/kg) followed by an infusion (2.5 mg/kg per hour for 4 of 6 hours, then 0.5 mg/kg per hour for 4 of 6 hours). The second study enrolled 8 volunteers with severe renal impairment who received a bivalirudin bolus of 1 mg/kg, followed by an infusion of 0.5 mg/kg per hour for 10 hours. Bivalirudin in plasma and urine was assayed with a newly developed, highly specific liquid chromatography-mass spectrometry assay.


RESULTS
Clearances at the two infusion doses did not differ significantly (3.23 mL/min per kilogram and 3.16 mL/min per kilogram). There was no statistically significant difference in area under the concentration-time curve (AUC) and in plasma clearance between patients with normal renal function and those with mild renal impairment. Patients with moderate and severe renal impairment had reductions in plasma clearance of 21% and 24%, respectively. The level of anticoagulation(activated clotting time) was similar between groups. There was no difference between male and female patients.


CONCLUSIONS
The clearance of bivalirudin is dependent on renal function but independent of dose and gender. Approximately 20% of unchanged drug is cleared via the kidney, and the remainder presumably undergoes proteolysis intracellularly. The pharmacodynamics of bivalirudin are dose-dependent and gender-independent. Bivalirudin kinetics are linear in the dose ranges that are used in percutaneous coronary intervention and that are under investigation for use in acute coronary syndromes.
Robson
Richard
R
Department of Nephrology, Christchurch Hospital, New Zealand.
White
Harvey
H
Aylward
Philip
P
Frampton
Christopher
C
D000368:Aged; D015906:Angioplasty, Balloon, Coronary; D000925:Anticoagulants / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D000991:Antithrombins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D005919:Glomerular Filtration Rate / Q000187:drug effects; D006629:Hirudins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D012727:Sex Characteristics; D013997:Time Factors
D000925:Anticoagulants; D000991:Antithrombins; D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; C074619:bivalirudin