Oral GPIIb / IIIa Antagonists: What Went Wrong?

Dermot      Cox

doi:10.2174/1381612043384673

Abstract

GPIIb / IIIa receptor antagonists block fibrinogen binding to platelets and as a result inhibit platelet aggregation. They are very potent inhibitors due to the critical role fibrinogen binding plays in platelet aggregation. When given intravenously these drugs have been shown to be very effective as adjuvant therapy in percutaneous coronary intervention and in acute coronary syndromes. However, despite being as potent as their intravenous counterparts, all of the oral inhibitors showed no benefit or even increased mortality in clinical trials. There are a number of reasons for their failure. The target was different, chronic treatment to prevent thrombotic events as opposed to short-term treatment to prevent acute events and as a result, different dosing regimens were used. The acute use aims for a high level of inhibition (80- 90%) while the chronic use produced lower levels of inhibition. Many of the oral inhibitors had low bioavailability that led to a large peak-trough difference. Most GPIIb / IIIa antagonists have the ability to activate platelets through a GPIIb / IIIa-mediated process. This is known as partial agonism. In the presence of high drug levels, such as during an infusion this is not a problem, however combined with the low trough levels with oral inhibitors this can lead to an increase in platelet aggregation. Other problems include drug-induced conformational changes in GPIIb / IIIa (ligandregulated binding sites) and possible pharmacogenomics effects in the response to the drugs, in particular the PlA polymorphism in GPIIb / IIIa. By addressing these issues it is possible for a new generation of oral GPIIb / IIIa antagonist to be developed.

Keywords: gpIIb IIIa antagonists, platelet aggregation, pharmacogenomics

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