Abciximab pharmacodynamics are unaffected by antecedent therapy with other GPIIb/IIIa antagonists in non-human primates.
BACKGROUND
Tirofiban and eptifibatide are currently approved for the medical stabilization of non-ST segment elevation acute coronary syndromes. In patients undergoing percutaneous coronary intervention (PCI) during infusion of these drugs, conversion to abciximab, which has long term proven clinical efficacy and cost-effectiveness, following PCI may be desirable. The purpose of this study was to determine if the binding or pharmacodynamics of abciximab is affected by a prior infusion of either tirofiban or eptifibatide.


METHODS
In vitro binding experiments were performed to determine if prior exposure to tirofiban or eptifibatide altered the affinity and extent of binding of abciximab to GPIIb/IIIa. For in vivo experiments, cynomolgus monkeys were pretreated with a bolus and 18 hour infusion of saline, tirofiban, or eptifibatide. At the end of the initial treatment, a bolus and 12 hr infusion of abciximab was started without delay. Inhibition of platelet aggregation, GPIIb/IIIa receptor blockade and abciximab pharmacokinetics were measured during and after both infusions.


RESULTS
Equilibrium binding of abciximab in vitro was unaffected by tirofiban or eptifibatide. The extent and duration of abciximab inhibition of ex vivo platelet aggregation, receptor blockade, and abciximab pharmacokinetics in monkeys during and after the abciximab infusion were not affected by prior infusion of the animals with tirofiban or eptifibatide.


CONCLUSIONS
In vitro and in vivo studies revealed that the molecular interaction of abciximab with the platelet GPIIb/IIIa receptor is not altered by immediate prior exposure of platelets to small molecule GPIIb/IIIa antagonists. These preclinical studies suggest that the efficacy of abciximab should not be impaired if it is initiated following termination of therapy with small molecule GPIIb/IIIa antagonists.
Nakada
Marian T
MT
Centocor, Malvern, PA 19355, USA. nakadam@centocor.com
Sassoli
Patricia M
PM
Tam
Susan H
SH
Nedelman
Mark A
MA
Jordan
Robert E
RE
Kereiakes
Dean J
DJ
D000077284:Abciximab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism* / Q000494:pharmacology*; D001666:Binding Sites, Antibody / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D000077542:Eptifibatide; D005260:Female; D007140:Immunoglobulin Fab Fragments / Q000378:metabolism* / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D010455:Peptides / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects / Q000276:immunology; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects / Q000276:immunology; D000077466:Tirofiban; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010455:Peptides; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D014443:Tyrosine; D000077466:Tirofiban; D000077542:Eptifibatide; D000077284:Abciximab