Introduction

Antiplatelet therapy remains a cornerstone in the management of patients with coronary artery disease. Beginning with aspirin monotherapy, antiplatelet therapy has evolved to include the administration of P2Y₁₂ receptor inhibitors in addition to aspirin. This dual antiplatelet therapy provides greater platelet inhibition, which leads to a reduction in recurrent ischemic events, albeit at the cost of increased bleeding complications [1, 2, 3].

Shortcomings of current therapy

The thienopyridines (e.g., ticlopidine, clopidogrel, and prasugrel) irreversibly inhibit the P2Y₁₂ receptor. While all of these agents lead to a reduction in recurrent ischemic events, they each have their associated shortcomings. Ticlopidine suffers from association with hypercholesterolemia and, more seriously, hematological effects, including neutropenia, aplastic anemia, and thrombotic thrombocytopenic purpura [4]. Clopidogrel is plagued by its delayed onset of action, interindividual pharmacokinetic and pharmacodynamic variability, and drug–drug interactions [5]. Furthermore, the platelet inhibition induced by clopidogrel is irreversible and increases the risk of major bleeding [1] as well as leads to potential prolonged hospitalization if clopidogrel is administered before the decision is made to pursue coronary artery bypass surgery. Prasugrel has less interindividual variability and faster onset of action and provides more potent platelet inhibition; however, it also suffers from an increase in major bleeding and causes irreversible platelet inhibition [3]. Ticagrelor, a noncompetitive and reversible inhibitor of the P2Y₁₂ receptor, reduces mortality, but there are concerns about increased fatal intracranial bleeding and risks of patient noncompliance given the fast offset of the drug [6, 7].

Pharmacological principles of elinogrel

Elinogrel, a novel, small-molecule, direct-acting, competitive, reversible, intravenous (IV) and oral quinazolinedione P2Y₁₂ receptor inhibitor (Portola Pharmaceuticals, San Francisco, CA, USA), has pharmacological properties that may address some of the limitations of current antiplatelet therapies. Elinogrel is synthesized from ethyl-5-chlorothiophen-2-ylsulfonylcarbamate and 3-(4-aminophenyl)-6-fluoro-7-(methylamino)quinazoline-2,4(1H,3H)-dione [8]. Notably, it exists in both oral and IV preparations without interactions at the level of the P2Y₁₂ receptor, allowing for ease of transition from IV to oral formulations without interruption in platelet inhibition. Prior studies have shown a drug interaction between the intravenously administered cangrelor and the orally administered thienopyridines (e.g., clopidogrel and prasugrel) [9], which leads to an inability of thienopyridine-induced platelet inhibition because the P2Y₁₂ receptor is already bound by cangrelor. Since both the oral and IV forms of elinogrel do not have these interactions at the level of the P2Y₁₂ receptor, sustained platelet inhibition is feasible even when transitioning from IV to oral dosing. In addition, elinogrel has a direct-acting mechanism of action without the need to be metabolized into an active form. Thus, in contrast to clopidogrel and prasugrel, which are both prodrugs, elinogrel avoids potential drug–drug interactions that result from reliance on the cytochrome P450 (CYP) system.

The elimination half-life of elinogrel is 11–12 h, time to peak 20 min, and offset 24 h. Clearance is mainly via hepatic demethylation and renal excretion. Twice daily dosing is required to maintain stable plasma concentrations.