Gretor 90 Mechanism of Action

Antithrombotic Agent (Platelet Aggregation Inhibitor Excl. Heparin).
Pharmacology: Pharmacodynamics: Mechanism of Action: Ticagrelor is a direct-acting, selective and reversibly binding P2Y₁₂ receptor antagonist that prevents adenosine diphosphate (ADP)-mediated P2Y₁₂ dependent platelet activation and aggregation. Since platelets participate in the initiation of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce risk of cardiovascular events such as CV death, Ml, or stroke. Ticagrelor also increases the local endogenous adenosine levels by inhibiting equilibrative nucleoside transporter-1 (ENT-1) prolonging the half-life of adenosine and thereby increases its local extracellular concentration by providing enhanced local adenosine responses (vasodilation, cardioprotection, platelet inhibition, modulation of inflammation, and induction of dyspnea).
Pharmacodynamic Effects: The benefits associated with Ticagrelor were independent of the use of other cardiovascular therapies including lipid-lowering drugs, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, Angiotensin II receptor antagonists (AIIRAs), calcium-channel blockers, nitrates, and proton pump inhibitors.
Pharmacokinetics: Ticagrelor demonstrates a linear pharmacokinetics and is approximately dose proportional with its active metabolite (AR-C124910XX).
Absorption: Absorption of ticagrelor occurs with a median tmax of 1.5 h (range 1.0 to 4.0). The formation of the major circulating metabolite AR-C124910XX (active) from ticagrelor occurs with a median tmax of 2.5 h (range 1.5 to 5.0). The mean absolute bioavailability of ticagrelor is about 36% (range 25.4% to 64%). Ingestion of a high-fat meal had no effect on ticagrelor Cmax but resulted in a 21% increase in AUC. The Cmax of its major metabolite was decreased by 22% with no change in AUC. Ticagrelor tablets as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and Cmax within 80 to 125% for ticagrelor and AR-C124910XX) with a median tmax of 1.0 hour (range 1.0 to 4.0) for ticagrelor and 2.0 hours (range 1.0 to 8.0) for AR-C124910XX.
Distribution: The steady state volume of distribution of ticagrelor is 87.5 L. Ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).
Metabolism: CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Ticagrelor and its major active metabolite are weak P-glycoprotein substrates and inhibitors. The systemic exposure to the active metabolite is approximately 30% to 40% of the exposure of ticagrelor.
Excretion: The primary route of ticagrelor elimination is hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in feces, 26.5% in urine). Recoveries of ticagrelor and the active metabolite in urine were both less than 1% of the dose. The primary route of elimination for the major metabolite of ticagrelor is most likely to be biliary secretion. The mean t_1/2 is approximately 6.9 hours for ticagrelor and 8.6 hours for the active metabolite.
Specific Populations: Elderly: Higher exposures of Ticagrelor (approximately 60%) and its active metabolite (approximately 50%) were observed in patients ≥65 years of age as compared with younger subjects. These differences are not considered clinically significant.
Pediatric Population: Ticagrelor has not been evaluated in pediatric population.
Gender: Higher exposures to Ticagrelor (approximately 52% for Cmax and 37% for AUC) and its active metabolite (approximately 50%) were observed in women compared to men.
Renal Impairment: Exposure to Ticagrelor was 20% lower and exposure to active metabolite was 17% higher in patients with severe renal impairment compared to subjects with normal renal function. In patients with end-stage renal disease on hemodialysis, Ticagrelor exposure were 38% AUC and 51% Cmax higher on a day without dialysis. A similar increase in exposure was observed immediately prior to dialysis showing that Ticagrelor is not dialysable. No dosing adjustment is required for patients with renal impairment.
Hepatic Impairment: Patient with mild hepatic impairment shows 12% Cmax and 23% AUC exposure to Ticagrelor. Ticagrelor has not been studied in patients with severe hepatic impairment and there is no pharmacokinetic information in patients with moderate hepatic impairment.
Ethnicity: Patients of Asian descent have a 39% higher mean bioavailability compared to Caucasian patients. Black had an 18% lower bioavailability of Ticagrelor. Hispanic and Latino were similar to that in Caucasians.