Agraplat Mechanism of Action

Pharmacology: Pharmacodynamics: Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12 ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.
Pharmacokinetics: Ticagrelor demonstrates dose proportional pharmacokinetics, which are similar in patients and healthy volunteers.
Absorption: Ticagrelor can be taken with or without food. Absorption of Ticagrelor occurs with a median tmax of 1.5 h (range 1.0-4.0). The formation of the major circulating metabolite AR-C124910XX (active) from Ticagrelor occurs with a median tmax of 2.5 h (range 1.5-5.0).
The mean absolute bioavailability of Ticagrelor is about 36% (range 30%-42%). 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 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 80-125% for Ticagrelor and AR-C124910XX) with a median tmax of 1.0 hour (range 1.0-4.0) for Ticagrelor and 2.0 hours (range 1.0-8.0) for AR-C124910XX.
Distribution: The steady state volume of distribution of Ticagrelor is 88 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 30-40% 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% (58% in feces, 26% 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 t½ is approximately 7 hours for Ticagrelor and 9 hours for the active metabolite.
Toxicology: Preclinical Safety Data: Preclinical data for Ticagrelor and its major metabolite have not demonstrated unacceptable risk for adverse effects for humans based on conventional studies of safety pharmacology, single and repeated dose toxicity and genotoxic potential.
Gastrointestinal irritation was observed in several animal species at clinical relevant exposure levels.
In female rats, Ticagrelor at high dose showed an increased incidence of uterine tumours (adenocarcinomas) and an increased incidence of hepatic adenomas. The mechanism for uterine tumours is likely hormonal imbalance which can lead to tumours in rats. The mechanism for the hepatic adenomas is likely due to a rodent-specific enzyme induction in the liver. Thus, the carcinogenicity findings are considered unlikely to be relevant for humans.
In rats minor developmental anomalies were seen at a maternal toxic dose (safety margin of 5.1). In rabbits a slight delay in hepatic maturity and skeletal development was seen in fetuses from dams at high dose without showing maternal toxicity (safety margin of 4.5).
Studies in rats and rabbits have shown reproductive toxicity, with slightly reduced maternal body weight gain and reduced neonatal viability and birth weight, with delayed growth. Ticagrelor produced irregular cycles (mostly extended cycles) in female rats, but did not affect overall fertility in male and female rats. Pharmacokinetic studies performed with radio-labelled Ticagrelor have shown that the parent compound and its metabolites are excreted in the milk of rats.