Pharmacokinetic and pharmacodynamic properties of eptifabatide in healthy subjects receiving unfractionated heparin or the low-molecular-weight heparin enoxaparin.
BACKGROUND
The rationale for the combined use of glycoprotein (GP) IIb/Illa inhibitors, such as eptifibatide, and antithrombin agents, such as unfractionated heparin (UFH), in patients presenting with non-ST-segment elevation (NSTE) acute coronary syndrome (ACS) and those scheduled for percutaneous coronary intervention is based on the fact that these therapies target the complementary pathophysiologic mechanisms responsible for ischemic adverse effects. The results of a recent study indicated that the combination of eptifibatide and enoxaparin is associated with a reduced rate of ischemic adverse effects compared with the combination of eptifibatide and UFH. Therefore, the coadministration of eptifibatide with enoxaparin is an attractive option for the management of patients with NSTE ACS.


OBJECTIVE
This study was designed to determine whether the substitution of enoxaparin for UFH, when coadministered with eptifibatide, affects the pharmacokinetic and pharmacodynamic properties of eptifibatide.


METHODS
This open-label, crossover study was conducted at the Quintiles Clinical Pharmacology Unit (Lenexa, Kansas). Healthy subjects were sequentially treated with the GP IIb-IIIa inhibitor eptifibatide (180 microg/kg bolus + 2.0 microg/kg.min infusion) plus UFH or eptifibatide plus the low-molecular-weight heparin enoxaparin, on 2 occasions, separated by a 6- to 14-day washout period. The order of administration of the 2 regimens was random. The primary end point of the study was the steady-state plasma concentration of eptifibatide (Css); secondary end points included the inhibition of platelet aggregation, area under the plasma-concentration time curve, apparent volume of distribution, plasma elimination half-life (t 1/2), and total body eptifibatide clearance (Cl).


RESULTS
A total of 14 subjects (10 men, 4 women; mean [SD] age, 53.2 [6.0]years) were enrolled. The mean (SD) Css of eptifibatide was essentially identical when it was coadministered with either UFH or enoxaparin (1640 [227] ng/mL and 1610 (229) ng/mL, respectively). In addition, no clinically significant differences were found between the coadministration of UFH versus enoxaparin in platelet aggregation inhibition, t 1/2, eptifibatide Cl, or other pharmacokinetic parameters. Both regimens were well tolerated; no serious adverse effects were reported.


CONCLUSIONS
The results in this population of healthy subjects, age-matched to the intended target population, suggest that eptifibatide can be used in the treatment of NSTE ACS effectively, with good tolerability, and without dose adjustment when coadministered with enoxaparin instead of with UFH.
Gretler
Daniel D
DD
Millennium Pharmaceuticals, Inc., 256 East Grand Avenue, South San Francisco, CA 94080, USA. dan.gretler@mpi.com
D000368:Aged; D019540:Area Under Curve; D002853:Chromatography, Liquid; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000077542:Eptifibatide; D005260:Female; D006207:Half-Life; D006493:Heparin / Q000494:pharmacology*; D006495:Heparin, Low-Molecular-Weight / Q000494:pharmacology; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D010455:Peptides / Q000493:pharmacokinetics* / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013997:Time Factors
D006495:Heparin, Low-Molecular-Weight; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D006493:Heparin; D013917:Thrombin; D000077542:Eptifibatide