Pharmacokinetic and Pharmacodynamic Effects of Elinogrel

Abstract

Background-Elinogrel is the only selective, competitive and reversible platelet P2Y 12 inhibitor available in both intravenous (IV) and oral formulations. Methods and Results-This substudy of the Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability andEfficacy in Nonurgent Percutaneous Coronary Intervention patients (INNOVATE-PCI) trial evaluated the pharmacokinetic and pharmacodynamic effects of two dosing regimens of IV followed by oral elinogrel (120 mg IV plus 100 mg oral twice daily; 120 mg IV plus 150 mg oral twice daily) versus standard clopidogrel therapy (300 -600 mg oral loading dose plus 75 mg oral maintenance dose) in 56 patients undergoing nonurgent PCI. At time of randomization, 71.4% (40/56) of patients were using maintenance clopidogrel therapy. In the acute phase, an IV bolus of elinogrel achieved more rapid and potent antiplatelet effects compared with clopidogrel, which were sustained during the transition from the IV to the oral formulation in the first 24 hours of the peri-PCI period. During chronic therapy, elinogrel achieved similar levels of platelet reactivity compared with clopidogrel before the next oral dose and, although platelet reactivity was lower with elinogrel up to 6 hours after daily oral maintenance dosing, these differences were not statistically significant. These pharmacodynamic effects matched the pharmacokinetic profile of elinogrel. There were no differences in pharmacodynamic and pharmacokinetic effects between the two elinogrel dosing regimens. Conclusions-Compared with clopidogrel, the combination of IV and oral elinogrel achieves more rapid and enhanced antiplatelet effects that were sustained through the transition to oral elinogrel in the peri-PCI period, but these were not significant during chronic dosing in this pilot investigation. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00751231.

New Directions in Antiplatelet Therapy

“…This trial provided promising results of elinogrel in terms of platelet inhibition, as both intravenous and oral dosing achieved greater and more rapid platelet inhibition than clopidogrel, and safety, as no significant increase in major bleedings was found. 71,72 A safety concern was the presence of elevated liver enzymes in 4.0% and 4.8% of the elinogrel 100 mg and 150 mg twice daily arms, respectively, mostly within the first 60 days, compared with 1% in the clopidogrel group. Phase III clinical evaluation of elinogrel is still pending.…”

“…Tato studie přinesla slibné výsledky elinogrelu ve smyslu inhibice krevních destiček, protože jak intravenózní, tak perorální podání vedlo k vyšší i rychlejší inhibici krevních destiček než v případě clopidogrelu, i k vyšší bezpečnosti, protože nebylo pozorováno významné zvýšení závažného krvácení. 71,72 Jisté obavy vyvolala přítomnost zvýšených koncentrací jaterních enzymů u 4,0 %, resp. 4,8 % pacientů v ramenech s elinogrelem v dávce 100 mg a 150 mg dvakrát denně, většinou v prů-běhu prvních 60 dní, oproti 1 % ve skupině s clopidogrelem.…”

Novel Antiplatelet Therapies for Atherothrombotic Diseases

“…Cangrelor had additionally been used off-label as a bridging therapy before cardiac surgery after discontinuation of thienopyridines, offering the potential advantage of rapid reversal of antiplatelet action with discontinuation 1 hour before surgery. 40 Additional evidence suggests that the benefits of cangrelor are maintained across several high-risk subgroups, including those with a history of stroke ≥1 year from the time of PCI, older patients, and in those on a background of anticoagulant therapy with heparin, without concomitant increases in the rates of major bleeding. 41–44…”

Prasugrel

“…In a different conceptual approach, researchers have attempted to link high-risk cohorts and worsened clinical outcomes to the degree of platelet inhibition by individual tailoring of antiplatelet therapy. However, trials, such as the Gauging Responsiveness With A VerifyNow Assay-Impact on Thrombosis And Safety (GRAVITAS), 5 Testing Platelet Reactivity In Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy With Prasugrel (TRIGGER-PCI), 6 Intravenous and Oral Administration of Elinogrel to Evaluate Tolerability and Efficacy in Nonurgent Percutaneous Coronary Intervention Patients (INNOVATE-PCI), 7 Assessment by a Double Randomization of a Conventional Antiplatelet Strategy Versus a MonitoringGuided Strategy for Drug-Eluting Stent Implantation and of Treatment Interruption Versus Continuation One Year After Stenting (ARCTIC), 8 The Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRIOLOGY-ACS), 9 and A Comparison of Prasugrel at PCI or Time of Diagnosis of Non--ST Elevation Myocardial Infarction (ACCOAST), 10 did not lend support to this notion. Lately, some differentiations emerged, for example, the insight by Salisbury et al 11 who have shown that the expected benefits and risks of prasugrel versus clopidogrel may depend on underlying patient characteristics.…”