Ticalor Mechanism of Action

Pharmacology: Mechanism of Action: Ticagrelor and its major metabolite reversibly interact with the platelet P2Y12ADP-receptor to prevent signal transduction and platelet activation. Ticagrelor and its active metabolite are approximately equipotent.
Pharmacodynamics: The inhibition of platelet aggregation (IPA) by ticagrelor and clopidogrel was compared in a 6 week study examining both acute and chronic platelet inhibition effects in response to 20 uM ADP as the platelet aggregation agonist. The onset of IPA was evaluated on Day 1 of the study following loading doses of 180 mg ticagrelor or 600 mg clopidogrel. IPA was higher in the ticagrelor group at all time points. The maximum IPA effect of ticagrelor was reached at around 2 hours and was maintained for at least 8 hours. The offset of IPA was examined after 6 weeks on ticagrelor 90 mg twice daily or clopidogrel 75 mg daily, again in response to 20 uM ADP, mean maximum IPA following the last dose of ticagrelor was 88% and 62% for clopidogrel. The insert shows that after 24 hours IPA in the ticagrelor group (58%) was similar to IPA in clopidogrel group (52%) indicating that patients who miss a dose of ticagrelor would still maintain IPA similar to the trough IPA of patients treated with clopidogrel after 5 days, IPA in the ticagrelor group was similar to IPA in the placebo group. It is not known how either bleeding risk of thrombotic risk with IPA for either ticagrelor or clopidogrel. Transitioning for clopidogrel to Ticalor resulted in absolute IPA increase of 26.4% and from ticagrelor to clopidogrel resulted in an absolute IPA decrease of 24.5%. Patients can be transitioned from clopidogrel to Ticalor without interruption of antiplatelet effect (see Dosage & Administration).
Pharmacokinetics: Ticagrelor demonstrates dose proportional pharmacokinetics. Which are similar in patients and healthy volunteers.
Absorption: Ticalor 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 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. Ticalor 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 2.0 hours (range 1.0-8.0) for AR-C124910XX.
Distribution: The steady state volume of distribution of ticagrelor and the active metabolite are extensively bound to human plasma proteins (>99%).
Metabolism: CYP3A4 is the 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 eliminations for the major metabolite of ticagrelor is most likely to be biliary secretion. The mean t_1/2 is approximately 7 hours for ticagrelor and 9 hours for the active metabolite.
Specific Populations: The effects of age, gender, ethnicity, renal impairment and mild hepatic impairment on the pharmacokinetics of ticagrelor are presented. Effects are modest and do not require dose adjustment. Patients with End-Stage Renal Disease on hemodialysis: AUC and Cmax of ticagrelor 90 mg administered on a day without dialysis were 38% and 51% higher respectively, compared to subjects with normal renal function. A similar increase in exposure was observed when ticagrelor is not dialyzable. Exposure of the active metabolite increased to a lesser extent. The IPA effect of ticagrelor was independent of dialysis in patients with end stage renal disease and similar to healthy adults with normal renal function.
Effects of their drugs on ticagrelor: CYP3A4 is the major enzyme responsible for ticagrelor metabolism and the formation of its major active metabolite. The effects of other drugs on the pharmacokinetics of ticagrelor are presented as change relative to ticagrelor given alone (test/reference). 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., cyclosporine) increase ticagrelor exposure. Co-administration of 5 mg intravenous morphine with 180 mg loading dose of ticagrelor decreased observed mean ticagrelor exposure by up to 25% in healthy adults and up to 36% in ACS patients undergoing PCI. Tmax was delayed by 1-2 hours. Exposure of the active metabolite decreased to as similar extent.
Morphine co-administration did not delay or decrease platelet inhibition in healthy adults. Mean platelet aggregation was higher up to 3 hours post loading dose in ACS patients co-administered with morphine. Co-administration of intravenous fentanyl with 180 mg loading dose of ticagrelor in ACS patients undergoing PCI resulted in similar effects on ticagrelor exposure and platelet inhibition.
Effects of ticagrelor on other drugs: In vitro metabolism studies demonstrate that 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. For specific in vivo effects on the pharmacokinetics of simvastatin, atorvastatin, ethinyl estradiol, levonorgestrel, tolbutamide, digoxin and cyclosporine.
Pharmacogenetics: In a genetic sub-study cohort of PLATO, the rate of thrombotic CV events in the Ticalor arm did not depend on CYP2C19 loss of function status.
Non Clinical Toxicology: Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Ticagrelor was not carcinogenic in the mouse at doses up to 250 mg/kg/day or in the male rat at doses up to 120 mg/kg/day (19 and 15 times the MHRD of 90 mg twice daily on the basis of AUC, respectively). Uterine carcinomas, uterine adenocarcinomas and hepatocellular adenomas were seen in female rats at doses of 180 mg/kg/day (29-fold the maximally recommended dose of 90 mg twice daily on the basis of AUC), whereas 60 mg/kg/day (8-fold the MHRD based on AUC) was not carcinogenic in female rats.
Mutagenesis: Ticagrelor did not demonstrate genotoxicity when tested in the Ames Bacterial mutagenicity test, mouse lymphoma assay and the rat micronucleus test. The active O-demethylated metabolite did not demonstrate genotoxicity in the Ames assay and mouse lymphoma assay.
Impairment of Fertility: Ticagrelor had no effect on male fertility at doses up to 180 mg/kg/day or on female fertility at doses up to 200 mg/kg/day (>15-fold the MHRD on the basis of AUC). Doses of ≥10 mg/kg/day given to female rats caused an increase incidence of irregular duration estrus cycle (1.5-fold the MHRD based on AUC).