Pharmacokinetic and pharmacodynamic properties of eptifibatide in subjects with normal or impaired renal function.
BACKGROUND
Previous studies of the glycoprotein IIb-IIIa inhibitor eptifibatide have included patients with moderate renal impairment (serum creatinine concentrations, 2.0-4.0 mg/dL). In these patients, adjustment of the standard infusion dose (2.0 microg/kg.min) to 1.0 microg/kg.min was recommended on empiric grounds because approximately 50% of eptifibatide is cleared renally.


OBJECTIVE
The present study was designed to assess teh pharmacokinetic and pharmacodynamic properties of eptifibatide in subjects with various levels of creatinine clearance (CrCl), a parameter that is a more accurate indicator of renal function than serum creatinine concentration to determine the appropriate dose adjustment in patients with reduced renal function. A secondary objective was to determine the tolerability of eptifibatide when administered to patients with decreased renal function.


METHODS
This open-label study was concluded at 3 US sites experienced in conducting similar studies. Subjects with differing renal function (normal [group 1, CrCl > 80 mL/min], mild renal impairment [group 2, CrCl 51-80 mL/min], moderate renal impairment [group 3, CrCl 30-50 mL/min], or severe renal impairment [group 4, CrCl <30 mL/min]) received a 24-hour eptifibatide infusion of 2.0 microg/kg.min (groups 1, 2, and 3) or 1.0 microg/kg.min (group 4). The primary end point was the eptifibatide steady-state plasma concentration; the secondary end points included inhibition of platelet aggregation and eptifibatide clearance, terminal plasma half-life, and area under the plasma concentration-time curve. In addition to analyses performed for each group, pharmacokinetic models were estimated and eptifibatide clearance was related to CrCl as a continuous variable by linear regression. All adverse events were recorded, with particular attention to bleeding.


RESULTS
Thirty-one subjects (21 men, 10 women; mean age, 58.5 years [range, 44-73 years]; mean body weight, 81.6 kg [range, 51.5-105.1 kg]; mean height, 162.9 cm [range, 150-183 cm]) were included in the study. A strong correlation was found between eptifibatide clearance and CrCl. A tree-based analytic model indicated that the optimal discrete break point for the purpose of dose adjustment was a CrCl of 55.85 mL/min, which was rounded to 50 mL/min for practical clinical reasons. In patients with moderate or severe renal impairment (CrCl < or = 50 mL/min), clearance rates and steady-state concentrations of eptifibatide were approximately 50% lower and almost 2-fold higher, respectively, than in patients with normal renal function or mild renal impairment (CrCl > 50 mL/min). Inhibition of platelet aggregation exceeded the clinically significant threshold of 80% in all groups. Five subjects had a mild bleeding event and 4 subjects experienced mild to moderate nonbleeding events, 2 of which were considered drug-related by the investigator. None of the events required intervention.


CONCLUSIONS
In this study, moderate to severe renal impairment was associated with an approximately 50% reduction in total eptifibatide clearance and a corresponding doubling of plasma eptifibatide concentration. Based on these findings, in patients with moderately or severely impaired renal function (calculated CrCl < or =50 mL/min) who are scheduled for percutaneous coronary intervention or who have non-ST-segment elevation acute coronary syndromes, it is appropriate to reduce the infusion dose of eptifibatide by 50% (from 2 to 1 microg/kg.min). Because the bolus dose(s) is (are) used to establish the initial targeted plasma eptifibatide concentrations, which are independent of clearance, and given that the volume of distribution did not correlate with renal function, no adjustment of the bolus dose(s) is required.
Gretler
Daniel D
DD
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.
Guerciolini
Roberto
R
Williams
Paul J
PJ
D000328:Adult; D000368:Aged; D003404:Creatinine / Q000378:metabolism; D000077542:Eptifibatide; D005260:Female; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D010455:Peptides / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D051437:Renal Insufficiency / Q000378:metabolism* / Q000503:physiopathology
D010455:Peptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D003404:Creatinine; D000077542:Eptifibatide