Pharmacokinetics and Pharmacodynamics of a Bolus and Infusion of Cangrelor: A Direct, Parenteral P2Y12 Receptor Antagonist

Abstract

The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers. Twenty-two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens: a 15-microg/kg bolus followed by a 2-microg/kg/min infusion or a 30-microg/kg bolus followed by a 4-microg/kg/min infusion. The infusion is continued for 60 minutes, and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters. Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes. Moreover, extensive platelet inhibition is maintained throughout the infusion period with near-full recovery of platelet function within 60 to 90 minutes of terminating the infusion. The effect of high-dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate-induced P-selectin expression; how ever, no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function. Cangrelor administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function.

Cangrelor inhibits the binding of the active metabolites of clopidogrel and prasugrel to P2Y12receptorsin vitro

“…Increasing the concentration of clopidogrel or prasugrel AM demonstrated that they have a limited ability to compete with cangrelor (1000 um/L) for binding to the P2Y 12 receptor. The data suggests that prasugrel AM may be better able to compete with cangrelor than clopidogrel AM despite both thienopyridine AMs having similar IC 50 values (0.30 mol/L) [16].…”

“…Cangrelor is a rapidly acting, direct-binding, reversible, intravenous P2Y 12 antagonist, which makes it attractive for use during percutaneous coronary intervention (PCI) in patients who may not have been sufficiently pretreated with an oral P2Y 12 antagonist, such as may occur in the management of acute ST-segment elevation myocardial infarction (STEMI) [1,2]. In the recent CHAMPION PHOENIX study, a bolus plus 2 hour infusion of cangrelor resulted in a decrease in ischaemic events during PCI with no increase in severe bleeding [3].…”

“…Cangrelor is administered intravenously at the time of PCI, however, since the risk of ischemic events persists after PCI, it is necessary to switch to an oral P2Y 12 antagonist such as clopidogrel, prasugrel or ticagrelor following the PCI. Clopidogrel and prasugrel are thienopyridine prodrugs that each require metabolism to their respective active metabolite (AM) which binds irreversibly to the P2Y 12 receptor.…”

“…Due to the irreversible binding of the thienopyridine active metabolites to platelet P2Y 12 receptors, the inhibitory effects of clopidogrel and prasugrel persist long after the relatively short-lived active metabolites have been cleared from plasma, and normal platelet function is not restored for up to 7 days post dose. As cangrelor is a direct-acting P2Y 12 antagonist it achieves steady state (401ng/ml, 0.5mol/L) within 2 minutes of bolus dosing [12] and has a shorter half-life (5 minutes) due to relatively rapid hydrolysis of cangrelor to its inactive metabolite [13]. Normal platelet function is restored 1-2 hours after cessation of cangrelor infusion as a result of the rapid fall in plasma cangrelor levels leading to dissociation of cangrelor from the P2Y 12 receptor [13].…”

“…Cangrelor was also found to limit the inhibition of platelet activation (measured by P selectin expression) by prasugrel AM in in vitro studies [15]. These previous studies have evaluated the ability of clopidogrel or prasugrel to inhibit platelet activation/aggregation in the presence of cangrelor as a surrogate measure of P2Y 12 receptor occupancy. In the in vitro studies described in this paper, we have directly measured the number of functional (unblocked) P2Y 12 receptors using a radioligand binding assay following co-incubation with cangrelor and either clopidogrel or prasugrel AM.…”