Introduction

Ticagrelor is a high affinity reversible P2Y₁₂ receptor inhibitor belonging to a new group of agents called cyclopentyltriazolopyrimidines. Because it is a direct-acting compound, further activation is not required unlike the irreversible P2Y₁₂ receptor inhibitor clopidogrel. Ticagrelor therefore results in consistent and fast onset platelet inhibition, while about 15–40% of individuals have high on-treatment platelet reactivity on clopidogrel [1, 2].

Mechanisms of action

Following oral administration, ticagrelor is rapidly absorbed and then directly inhibits the P2Y₁₂ receptor in a reversible manner. It undergoes enzymatic degradation mainly by CYP3A4 to one pivotal active metabolite, which has the same pharmacokinetics as the parent compound and a systemic exposure of 30–40% out of the parent compound. Ticagrelor’s direct inhibition of the P2Y₁₂ receptor makes it more potent and faster acting than clopidogrel [2].

Ticagrelor treatment resulted in a lower incidence of cardiovascular deaths, myocardial infarction (MI), and stroke compared with clopidogrel treatment, irrespective of polymorphism of CYP2C19 and ABCB1 in a genetic substudy of the multicenter phase 3 trial PLATelet inhibition and patient Outcomes (PLATO). This indicates less influence of CYP polymorphism upon ticagrelor treatment than on clopidogrel treatment [1].

Pharmacodynamics

Treatment with ticagrelor results in significant faster, greater, and more consistent platelet inhibition than treatment with clopidogrel. In a substudy of the phase 2b dose-guiding Dose confirmation Study assessing anti-Platelet Effects of AZD6140 vs. clopidogRel in non-ST-segment Elevation myocardial infarction (DISPERSE)-2 trial, a loading dose (LD) of 180 mg ticagrelor resulted in a maximum of 50–60% inhibition of platelet aggregation within 2–4 h. This degree of inhibition was sustained during maintenance therapy with 90 mg twice a day (bid). The most consistent response was seen in the group taking ticagrelor 180 mg bid. Further platelet inhibition was gained when patients switched from clopidogrel to ticagrelor treatment regardless of high or low platelet inhibition response while on clopidogrel [3].

Ticagrelor and its active metabolite are primarily excreted in feces (57.8%) and to a minor extent in urine (26.5%) [4]. Compared to healthy individuals, the exposure to ticagrelor and its main metabolite is higher in patients with renal impairment (glomerular filtration rate <30 mL/min) and in those with mild hepatic impairment. This seems to lack clinical importance since the unbound fraction and the fraction of platelet aggregation inhibition are the same as in control populations [5, 6].