Pharmacology: 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: The AUC0-t for the test drug was 4356.26 ng.hour/ml. The AUC0-inf for the test drug was 4561.14 ng.hour/ml. The Cmax for the test drug was 726.95 ng/ml.
The geometric mean ratios (90% confidence intervals) of the test drug/comparator drug for ticagrelor were 107.12% (99.75-115.03%) for AUC0-t and 111.02% (101.48-121.46%) for Cmax. The 90% confidence intervals of the test/comparator ratios for both AUC0-t and Cmax of ticagrelor were within the acceptance range for bioequivalence.
The mean (SD) elimination half-life (t½) of ticagrelor for the test drug was 6.22 (0.84) hours. The half-life values of the test and the comparator drug were not significantly different.
The median (range) of the time to reach maximum ticagrelor plasma concentration (tmax) of the test drug was 1.50 (1.00-4.00) hours. The tmax values of the test drug and the comparator drug were not significantly different.
Special populations: The effects of age, gender, ethnicity, renal impairment, and mild hepatic impairment on the pharmacokinetics of ticagrelor are modest and do not require dose adjustment.
Pediatric: Ticagrelor has not been evaluated in a pediatric population (see Use in specific populations under Precautions).
Body weight: No dose adjustment is necessary for ticagrelor based on weight.
Smoking: Habitual smoking increased population mean clearance of ticagrelor by approximately 22% when compared to non-smokers. No dose adjustment is necessary for ticagrelor based on smoking status.
Effects of other drugs on ticagrelor: CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, and clarithromycin) substantially increase ticagrelor exposure. Moderate CYP3A inhibitors have lesser effects (e.g., diltiazem). CYP3A inducers (e.g., rifampin) substantially reduce ticagrelor blood levels. P-gp inhibitors (e.g., ciclosporin) increase ticagrelor exposure.
Effects of ticagrelor on other drugs: Ticagrelor and its major active metabolite are weak inhibitors of CYP3A4, potential activators of CYP3A5 and inhibitors of the P-gp transporter. Ticagrelor and AR-C124910XX were shown to have no inhibitory effect on human CYP1A2, CYP2C19, and CYP2E1 activity.
Pharmacogenetics: The rate of thrombotic cardiovascular events in the ticagrelor arm did not depend on CYP2C19 loss of function status.