Absorption, Distribution, Metabolism, and Excretion of Ticagrelor in Healthy Subjects
ABSTRACT Ticagrelor [(1S,2S,3R,5S)-3-[7-[[(1R,2S)-2-(3,4-difluorophenyl) cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-1,2-cyclopentanediol)] is a reversibly binding oral P2Y(12) receptor antagonist in development for the prevention of thrombotic events in patients with acute coronary syndromes. The pharmacokinetics, metabolism, and excretion of ticagrelor were investigated over 168 h in six healthy male subjects receiving a single oral suspension dose of 200 mg of [(14)C]ticagrelor. Ticagrelor was rapidly absorbed with a maximum plasma concentration at 1.5 h. The major active metabolite, AR-C124910XX, is formed by O-deethylation. Exposure to AR-C124910XX was 29% of peak and 40% of overall exposure to ticagrelor. In most subjects, radioactivity was undetectable in plasma after 20 h and whole blood after 12 h (half-life values of 6.3 and 4.6 h, respectively). The ratio of radioactivity in plasma to whole blood was 1.69, suggesting that ticagrelor and its metabolites are largely restricted to the plasma space. Mean radioactivity recovery was 26.5% in urine and 57.8% in feces. Major circulating components in the plasma and feces were identified as ticagrelor and AR-C124910XX, whereas in urine the major components were metabolite M5 (AR-C133913XX) and its glucuronide conjugate M4. Levels of unchanged ticagrelor and AR-C124910XX were <0.05% in the urine, indicating that renal clearance of ticagrelor and AR-C124910XX is of minor importance. Interindividual variability was small in both urine and fecal extracts with only small quantitative differences. All 10 of the metabolites were fully or partially characterized and a full biotransformation pathway was proposed for ticagrelor, in which oxidative loss of the hydroxyethyl side chain from ticagrelor forms AR-C124910XX and a second oxidative pathway leads to N-dealkylation of ticagrelor, forming AR-C133913XX.
- SourceAvailable from: Tong Liu
International journal of cardiology 08/2015; 192:11-13. DOI:10.1016/j.ijcard.2015.05.023 · 4.04 Impact Factor
- "Sudden onset of gouty arthritis mainly results from a rapid rise or fall in serum uric acid, as well as inflammation caused by uric acid crystallization. Ticagrelor, as a reversibly binding P2Y 12 receptor antagonist, is rapidly absorbed  and metabolized . AR-C124910XX, the major metabolite which it rapidly formed, has a potency approximately equal to that of ticagrelor , but with a little difference existing as well. "
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- "On average, the median time to maximum concentration of ticagrelor is approximately 2 hours for healthy volunteers and patients with CAD and is slightly extended at 3 hours for patients with ACS.12–18 The half-life of ticagrelor is 7–8.5 hours and 8.5–10 hours for its main active metabolite (AR-C124910XX), with excretion through the urine and feces.12,13 Ingestion of food has a minimal effect on the pharmacokinetic profile of ticagrelor and its major metabolite, thus can be taken without regard to meals.19 "
ABSTRACT: Antiplatelet therapy is widely used with proven benefit for the prevention of further ischemic cardiac complications in patients with acute coronary syndrome. Treatment guidelines for acute coronary syndrome and percutaneous coronary intervention now recommend the use of oral antiplatelet agents including ticagrelor, prasugrel, or clopidogrel in combination with aspirin to comprise dual antiplatelet therapy for the prevention of recurrent ischemic events. The limitations of conventional antiplatelet therapy with clopidogrel or prasugrel include the potential for low response to clopidogrel identified through platelet reactivity or genetic testing, increased risk of bleeding with prasugrel, or slower return to normal platelet activity in patients who received either prasugrel or clopidogrel prior to emergent or planned surgical procedures. This review will discuss the pharmacokinetic and pharmacodynamic properties of ticagrelor in comparison to conventional P2Y12 receptor inhibitors and its utility in patients identified as low responders to clopidogrel. Completed clinical studies and substudies comparing ticagrelor to clopidogrel and ongoing clinical trials evaluating ticagrelor in acute coronary syndrome patients will also be reviewed.Clinical Pharmacology: Advances and Applications 04/2013; 5:67-83. DOI:10.2147/CPAA.S41859
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ABSTRACT: Purpose Ticagrelor, a reversibly binding oral P2Y12 receptor antagonist, is predominantly metabolized by cytochrome P450 3A and both the parent compound and its active metabolite AR-C124910XX are substrates of P-glycoprotein. Rifampicin was used to assess the effects of CYP3A and P-glycoprotein induction on the single-dose pharmacokinetics and pharmacodynamics of ticagrelor. Methods Healthy volunteers received a single 180 mg oral dose of ticagrelor on days 1 and 15, and a once-daily 600 mg dose of rifampicin on days 4–17. Ticagrelor and AR-C124910XX plasma concentrations were quantified for pharmacokinetic analysis (n = 14); inhibition of platelet aggregation (IPA) was also assessed (n = 14). Results Compared with administration of ticagrelor alone, co-administration of ticagrelor and rifampicin significantly decreased the maximum plasma concentration (Cmax) of ticagrelor from 1091 to 297.8 ng/ml, area under the plasma concentration-time curve from time zero to infinity (AUC) of ticagrelor from 6225 to 864.0 ng.h/ml, and also decreased plasma half-life of ticagrelor from 8.4 to 2.8 h; reductions of 73 %, 86 % and 67 % respectively. With rifampicin, AR-C124910XX Cmax was unaffected, AUC was significantly decreased by 46 %, and metabolite to parent ratio for AUC increased fourfold. Although maximal IPA was unaffected, offset of ticagrelor-mediated IPA was more rapid in the presence of rifampicin; a significant reduction (27 %) in the area under the effect curve between 0 and 24 h was observed following co-administration with rifampicin. Conclusion Co-administration with rifampicin reduced ticagrelor exposure and resulted in a more rapid offset of ticagrelor-mediated IPA. Co-administration of strong CYP3A/P-glycoprotein inducers with ticagrelor should be discouraged.European Journal of Clinical Pharmacology 10/2012; 69(4). DOI:10.1007/s00228-012-1436-x · 2.97 Impact Factor