New Drugs Antiplatelets-Antithrombotics - John Fanikos, RPh, MBA ...

Pharmacodynamic Properties of P2Y 12 InhibitorsPharmacodynamic Properties of P2Y 12 InhibitorsClopidogrelPrasugrelTicagrelor*Cangrelor*Elinogrel*ClopidogrelPrasugrelTicagrelor*Cangrelor*Elinogrel*RouteOralOralOralIVOral/IVRouteOralOralOralIVOral/IVReceptor BindingIrreversibleIrreversibleReversibleReversibleReversibleReceptor BindingIrreversibleIrreversibleReversibleReversibleReversiblePro-drugMetabolismYesCYP 3A4/52B6, 2C9,2C19YesCYP 3A4,2B6, 2C9,2C19*Investigational Agent, ** Active metabolite half-lifeMetabolicPathwaysNoCYP 3A4NoPlasmaesteraseNoNot ReportedPro-drugMetabolismClearanceEnteral BioavailabilityTime to peak plateletinhibitionPlasma half lifeDuration of antiplateleteffectDrug Interactions orgenetic polymorphismsYesCYP 3A4/52B6,2C9,2C19Renal 50%Fecal 46%50%300mg LD:6hrs600mg LD:2hrs8 hours**7 - 10 daysYesRenal 68%Fecal 27%1 - 2 hours8 hours**7 - 10 days*Investigational Agent, ** Active metabolite half-lifeYesCYP 3A4,2B6,2C9,2C1980%NoNoCYP 3A4Renal 1%NotReported2 hours6 - 12 hours1 dayNoNoPlasmaesterase-IV only30 mins3 - 9 mins20 - 60 minsNotReportedNoNot ReportedRenal 52%Fecal 48%Not Reported20 mins (IV)12 hours1 dayNot ReportedK Anger et al Irwin and Rippes Crit Care Med.8th EditionIndividual Response Variability to Dual AntiplateletTherapy in the Steady State Phase of TreatmentBalance ofEfficacy and SafetyNumber of Patients2015105Bleeding riskIschemic riskEndpoint (%)1510CV Death / MI / StrokeClopidogrel12.1Prasugrel9.9138eventsHR 0.81(0.73-0.90)P=0.0004NNT = 460Adapted from Angiolillo DJ et al. Am J Cardiol.2006;97:38-43.2.512.522.532.542.552.562.572.582.592.57.517.527.537.547.557.567.577.587.597.5% Platelet Aggregation (LTA-ADP ADP 20µmol/L)5TIMI MajorNonCABG BleedsPrasugrelClopidogrel00 30 60 90 180 270 360 450Days2.41.835eventsHR 1.32(1.03-1.68)P=0.03NNH = 167PLATO study designNSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;randomised within 24 hours of index event(N=18,624)ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)6–12-month exposurePrimary endpoint: CV death + MI + StrokePrimary safety endpoint: Total major bleedingPCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;CV = cardiovascular; TIA = transient ischaemic attackTicagrelor180 mg loading dose, then90 mg bid maintenance;(additional 90 mg pre-PCI)Hierarchical testing major efficacy endpointsAll patients*Ticagrelor Clopidogrel(n=9,333) (n=9,291)HR for(95% CI) p value †Primary objective, n (%)CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92)