Ticalor Mechanism of Action

Pharmacology: Pharmacodynamics: Ticagrelor, a member of the chemical class cyclopentyltriazolopyrimidines (CPTP), which is an oral, direct acting, selective and reversibly binding P2Y₁₂ receptor antagonist that prevents adenosine diphosphate (ADP)-mediated P2Y₁₂ dependent platelet activation and aggregation. Ticagrelor does not prevent ADP binding, but when bound to the P2Y₁₂ receptor prevents ADP-induced signal transduction. Since platelets participate in the initiation and/or evolution of thrombotic complications of atherosclerotic disease, inhibition of platelet function has been shown to reduce the risk of CV events such as death, MI or stroke.
Onset and Offset of Action: Onset of pharmacological effect as demonstrated by a mean inhibition of platelet aggregation (IPA) for ticagrelor is at 0.5 hours after 180 mg loading dose of about 41%, with the maximum IPA effect of 87.9% to 89.6% by 2-4 hours post dose. 90% of patients had final extent IPA >70% by 2 hours post dose. The high IPA effect of ticagrelor between 87%-89% was maintained between 2-8 hours.
Ticagrelor has a faster rate of offset of IPA as compared to clopidogrel as determined by the slope of offset from 4-72 hours after last dose. Median final extent IPA measured after the last dose of ticagrelor is approximately 20-30% higher for ticagrelor compared to clopidogrel.
Pharmacokinetics: Absorption: Absorption of ticagrelor is rapid with a median t_max of approximately 1.5 hours. The formation of the major circulating metabolite AR-C124910XX (also active) is rapid with a median t_max of approximately 2.5 hours. The C_max and AUC of ticagrelor and the active metabolite increased in an approximately proportional manner with dose over the dose range studied (30-1260 mg).
The mean absolute bioavailability of ticagrelor was estimated to be 36% (range 25.4% to 64.0%). Ingestion of a high-fat meal had no effect on ticagrelor C_max of the AUC of the active metabolite, but resulted in a 21% increase in ticagrelor AUC and 22% decrease in the active metabolite C_max. These small changes are considered of minimal clinical significance; therefore, ticagrelor can be given with or without food.
Ticagrelor as crushed tablets mixed in water, given orally or administered through a nasogastric tube into the stomach, is bioequivalent to whole tablets (AUC and C_max within 80-125% for ticagrelor and the active metabolite). Initial exposure (0.5 and 1 hour post-dose) from crushed ticagrelor tablets mixed in water was higher compared to whole tablets, with a generally identical concentration profile thereafter (2 to 48 hours).
Distribution: The steady state volume of distribution of ticagrelor is 87.5 L. Ticagrelor and the active metabolite is extensively bound to human plasma protein (>99.0%).
Metabolism: CYP3A is the major enzyme responsible for ticagrelor metabolism and the formation of the active metabolite and their interactions with other CYP3A substrates ranges from activation through to inhibition. Ticagrelor and the active metabolite are weak P-glycoprotein inhibitors.
The major metabolite of ticagrelor, which is also active as assessed by in vitro binding to the platelet P2Y₁₂ ADP-receptor. The systemic exposure to the active metabolite is approximately 30-40% of that obtained for ticagrelor.
Excretion: The primary route of ticagrelor elimination is via hepatic metabolism. When radiolabeled ticagrelor is administered, the mean recovery of radioactivity is approximately 84% (57.8% in faeces, 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 active metabolite is mostly via biliary secretion. The mean t_½ was approximately 6.9 hours (range 4.5-12.8 hours) for ticagrelor and 8.6 hours (range 6.5-12.8 hours) for the active metabolite.
Pharmacokinetics in Special Population: Elderly: Higher exposures to ticagrelor (approximately 60% for both C_max and AUC) and the active metabolite (approximately 50% for both C_max and AUC) were observed in elderly (≥65 years) subjects compared to younger subjects. These differences are not considered clinically significant.
Pediatric: Ticagrelor has not been evaluated in a pediatric population.
Sex: Higher exposures to ticagrelor (approximately 52% and 37% for C_max and AUC, respectively) and the active metabolite (approximately 50% for both C_max and AUC) were observed in women compared to men. These differences are not considered clinically significant.
Renal Impairment: Exposure to ticagrelor was approximately 20% lower and exposure to the active metabolite was approximately 17% higher in patients with severe renal impairment compared to subjects with normal renal function. The IPA effect of ticagrelor was similar between the two groups, however there was more variability observed in individual response in patients with severe renal impairment. No dosing adjustment is needed in patients with renal impairment. No information is available concerning treatment of patients on renal dialysis.
Hepatic Impairment: C_max and AUC for ticagrelor were 12% and 23% higher in patients with mild hepatic impairment compared to matched healthy subjects, respectively, however the IPA effect of ticagrelor was similar between the two groups. No dose adjustment is needed for patients with mild hepatic impairment. Ticagrelor has not been studied in patients with moderate or severe hepatic impairment.
Race: Patients of Asian descent have a 39% higher mean bioavailability compared to Caucasian patients. Patients self-identified as Black had an 18% lower bioavailability of ticagrelor compared to Caucasian patients. In clinical pharmacology studies, the exposure (C_max and AUC) ticagrelor in Japanese subjects was approximately 40% (20% after adjusting for body weight) higher compared to that in Caucasians.