Ticagrelor: The first approved reversible oral antiplatelet agent.

Platelet aggregation plays an important role in the pathophysiology of acute coronary syndrome (ACS). Aspirin is the most widely used antiplatelet agent and acts by inhibiting thromboxane A2-induced platelet activation. But it does not prevent platelets activation and aggregation by other signaling pathways like adenosine diphosphate (ADP) and Glycoprotein IIb/IIIa. Ticagrelor is the first oral reversible ADP (P2Y12) receptor antagonist. As compared to clopidogrel, ticagrelor has rapid onset as well as offset of action because of its reversible binding to P2Y12 receptor. It has potential to change the standard drug therapy of patient of ACS as shown in Platelet inhibition and patient outcomes (PLATO) trial, but long-term studies are required to further evaluate its efficacy and safety in these patients.

INTRODUCTION

Platelet aggregation at the sites of atherosclerotic plaque rupture initiates the cascade leading to atherothrombosis resulting in myocardial infarction, stroke etc., Thus, anti-platelet therapy remains cornerstone of antithrombotic therapy in patients suffering from acute coronary syndrome (ACS).[1] Different pharmacotherapeutic agents acting through different mechanism of action can be used, as platelet activation is a multifaceted process.[2] Now a days, a dual antiplatelet therapy of clopidrogel and aspirin is widely used for synergistic platelet inhibition.[2] However, thienopyridine i.e., clopidrogel, the most widely used P2Y12-type adenosine diphosphate (ADP) receptor inhibitor has number of limitations – being irreversible inhibitor of P2Y12 receptors, it carries increase risk of bleeding; being a prodrug, it requires hepatic conversion to an active metabolite resulting in delayed onset of action and inter-individual variability.[34]

Prasugel, a new thienopyridine agent, is more efficiently metabolized to its active metabolite, however, the risk of major bleeding episodes and life-threatening hemorrhages are higher for patients taking prasugrel compared to those taking clopidrogel.[4]

To overcome the drawbacks of the thienopyridine group of antiplatelet agents, ticagrelor first drug of a new chemical class called cyclopentyl-triazolo-pyrimidine is designed.[5] It has unique pharmacological properties: It is a reversible inhibitor of P2Y12 receptor, so the effects can be reversed more easily; it is not a prodrug, therefore, does not require metabolic activation resulting in rapid onset of action with less inter-individual variation;[5] it also inhibits non-platelet P2Y12 receptor present on vascular smooth muscles, where they cause vasoconstriction and increases myocardial perfusion.[5-7]

MECHANISM OF ACTION

ADP plays an important role in platelet aggregation by acting on P2Y1 and P2Y12 receptors on the surface of platelets. Inhibition of either of the receptors is sufficient to block platelet activation.[5] Ticagrelor binds to an area distinct from the ADP binding site, and inhibits ADP-induced receptor activation in a non-competitive manner. As compared to ticagrelor, clopidrogel binds covalently to ADP binding site and renders the receptor permanently inactivated. Whereas, ticagrelor leaves the receptor intact upon dissociation, thus inhibition of platelet aggregation is reversible.[6]

Ticagrelor prevents vasospasm by inhibiting activation of P2Y12 receptor-induced vasoconstriction. Ticagrelor also prevents restenosis by inhibiting P2Y12 receptor-induced inflammation. In comparison, these effects are not seen with thienopyridines, as they cannot penetrate vascular wall owing to their physical and chemical properties.[6]

In addition, ticagrelor increases myocardial blood flow by inhibiting uptake of adenosine by erythrocytes and provides additional benefit to the patients of ACS.[8]

PHARMACOKINETICS

Ticagrelor is rapidly absorbed from the gut after oral administration and reaches peak plasma concentration in around 1.5 hours. Its bioavailability is around 36%. It is mainly metabolized to active metabolite via cytochrome enzymes.[69] The concentration of this active metabolite is approximately 30-40% of ticagrelor. The pharmacokinetics of ticagrelor and its active metabolite are predictable up to 1260 mg dose (seven fold daily dose). Both ticagrelor and its active metabolite show plasma protein binding greater than 99.7%, and they are mainly excreted via bile and feces.[9]

CLINICAL TRIALS

The efficacy and safety of ticagrelor have been evaluated by Platelet inhibition and Patient Outcomes (PLATO) phase-III trial. The PLATO trial was performed in patients with either non-ST elevation or ST-elevation ACS. A total of 18,624 patients were randomly assigned to receive either ticagrelor (180 mg loading dose, 90 mg twice daily thereafter) or clopidrogel (300-600 mg loading dose, 75 mg thereafter) along with aspirin (75-100 mg per day) for 12 months. The primary efficacy outcome was the death from cardiovascular causes. Myocardial infarction or stroke was significantly reduced among patients who received ticagrelor compared with those who took clopidrogel (9.8% versus 11.7%; hazard ratio (HR) 0.84, P < 0.001).[1011]

However, one group of patients enrolled in United States fared worse with ticagrelor as compared of clopidrogel (hazard ratio 1.27 as compared to hazard ratio for non US patients: 0.81). PLATO data showed that aspirin dosage was ≥300 mg in this subgroup of patients and that might be reason for this type of response.[10]

ADVERSE EFFECTS

The most common adverse event during PLATO clinical trial was dyspnea. It is thought this effect may be due to its action on uptake of adenosine.

Various types of bleeds, i.e., gastrointestinal, intracranial, and dermal, had been seen. Rate of major bleed was similar between the ticagrelor and clopidrogel groups (P = 0.43), but rate of major bleeding not related to coronary artery bypass graft surgery was higher with ticagrelor (P = 0.03). Furthermore, ticagrelor was reported to have higher incidences of ventricular pauses in the first week of treatment but difference did not persist by 30 days.[1011] Other adverse effects reported with ticagrelor were headache, nausea, dyspepsia, insomnia, dizziness, syncope, and hypotension.[10]

DRUG-INTERACTIONS

Ticagrelor is both substrate as well as inhibitor of CYP450 enzymes. CYP450 inhibitors and CYP450 inducers can significantly increase or decrease ticagrelor plasma concentration.

In addition, ticagrelor and its active metabolite are both substrate as well as inhibitor of P-glycoprotein. It has been shown to significantly increase plasma digoxin concentration by inhibiting P-glycoprotein.[11]

CURRENT STATUS

Ticagrelor has been approved by FDA in July 2011 in patients suffering from ACS, it is available as 90 mg tablet; given as single 180 mg oral loading dose followed by a twice-daily 90 mg maintenance dose along with maintenance dose of 75-100 mg aspirin. It has been approved for marketing in India by drug controller general in may 2012.