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

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Anti Xa Agents: ComparativePharmacokinetics & PharmacodynamicsDrugAbsorptionApixaban Rivaroxaban Edoxaban Betrixaban LY 517717 YM150(BMS) (Ortho) DU 176B (Portola/BMS) (Lilly) (Astellas)(Daiichi-Sankyo)• Reaches steady • Reaches • Reaches • Reaches steady • Reaches steady • Notstate within steady state steady state state within 72h state in 80 reported48hrwithin 24h within 24h • Peak to trough hours• Peak to trough • Peak to trough • Peak to ratio of 3.5:1 • 82% relativeratio of 5.5:1 Ratio 10:1 trough Ratio • 47% relative bioavailability• 66% relative • 80% relative 13:1bioavailabilitybioavailability. bioavailability. • 50% relative • Reduction in AUC• Delayed bioavailability and Cmax withabsorption .mealswith food• Half life of 8- • Half life of 9-Clearance & 15hr13hMetabolism • 25% renally • 66% renallycleared cleared.• Potent CYP3A4 • PotentPotential Drug inhibitors inhibitors of-DrugCYP3A4 andInteractionPGP• Half life of 9- • Half life of 19hr11hr• 5-10% renally• Mainly renally clearedcleared.• Potent • Low potentialCYP3A4inhibitors• Half life 25 hr • Not• Primarily reportedGastrointestinal• Not reported • NotreportedEriksson BI et al. Clin Pharmacokinet 2009;48(1):1-22Betrixaban Phase II Trial: EXPLORE-XaXaBetrixaban40 mg DailyNon Valvular Atrial Fibrillation561 Patients1:1:1:1Betrixaban60 mg DailyR3 months>1 Risk FactorsOver 75 years Prior CVACHFCADHypertension DiabetesBetrixaban80 mg DailyMajor, Clinically Relevant BleedingWarfarin INR2-31 Event 4 Events 5 Events 5 EventsEzekowitz MD et al. Present at the Amer Coll of Cardiology, Atlanta GA 2010YM150, as Prophylaxis for VTE in Patients withElective Primary Hip Replacement SurgeryMethods:• A randomized, enoxaparincontrolled,dose escalation study• Performed in 174 patientsundergoing elective primary hipreplacement surgery• Assessed the safety and efficacyof 7-10 days of treatment with oraldoses of YM150– (3, 10, 30, or 60 mg once dailystarting 6-10 h after surgery)– With s.c. enoxaparin (40 mg oncedaily starting 12 h before surgery)YM1503mg qdYM15010mg qdYM15030mg qdYM15060mg qdEnoxaparinMinorbleeds2.9%5.7%No trendNo trend22%Eriksson B.I., et al. Journal of Thrombosis & Haemostasis 2007; 5(8):1660-5.VTE52%39%23%19%39%Injectable Novel Agents: ComparativePharmacokinetics & PharmacodynamicsTargetDirectInhibitionRouteHalf-LifeRenalClearance• IIa• Yes• IV• 25 Min• 20%Routine • NoMonitoringAntidoteBivalirudin• No• IIa• Yes• SC• 6 hours• 100%• No• NoDesirudinBiotinylatedIdraparinux• Xa • Xa• No • Yes• SC• 17 hours• 100%• No• AvidinWeitz J et al. Lancet 2009;374:762-764Otamixaban• IV• 30 Min•
BOREALIS-AFBiotinylated IdraparinuxCASSEOPEIANon-Valvular AFPrior Stroke or TIA>2 Risk factorsSymptomaticPulmonaryEmbolism+/- DVTRRWarfarin INRadjustedOnce DailyBiotinylatedIdraparinux 3.0mgOnce WeeklyEnoxaparin 1 mg per kg dailyWarfarin INRadjustedOnce DailyBiotinylatedIdraparinux 3.0mgOnce Weekly1. All strokes or non CNSsystemic embolic events2. Major Bleeding or Death1. Recurrence of VTE at 3 and 6months2. Major BleedingPatients Reaching PrimaryEndpoint in 7 DaysDEATH OR MI in 7 Days65432108765432107.24.6SEPIA-ACS1 TIMI 42 Results3.8 3.60.035 0.07 0.105 0.14 0.175 UFH+Ept4.8Death, MI, UrgentRevascularization2.8Dose (mg/kg/hr)4.3RR vs 1.16 0.74 0.61 0.58 0.69ControlDeath or MI at 7 Days2.6 2.7 2.80.035 0.07 0.105 0.14 0.175 UFH+EptDose (mg/kg/hr)RR vs 0.98 0.57 0.52 0.56 0.58Control6.24.9Patients with ThromboticComplications During PCITIMI Major and MInorBleeding7654321065432106.2Thrombotic ComplicationsDuring PCI52.90.035 0.07 0.105 0.14 0.175 UFH+Ept1.6 1.63.5Dose (mg/kg/hr)3.10.035 0.07 0.105 0.14 0.175 UFH+Ept3.4Dose (mg/kg/hr)3.2RR vs 2.52 2.06 1.17 1.44 1.31ControlMajor or Minor BleedingRR vs 0.61 0.61 1.15 1.26 2.02ControlSabatine M. et al. Lancet 2009;374:787-7955.42.42.7REG1 Anticoagulation System• Comprisedof anaptamerbasedanticoagulant• RB006, &its matchedantidote,RB007REG1AnticoagulationSystem• Comprised of anaptamer-basedanticoagulant• Protein bindingoligonucleotide• Direct IXainhibitor•RB006, & itsmatched antidote,RB007Dyke CK. Circulation2006:114:2490-2497Baseline DataStudyDrugTimeline of ProceduresInformed consent will be executed prior to administration of any sedativesClopidogrel 600 mg loading dose and ASA 250-500 mg at least 4 hours prior to PCIPatients who receive heparin during diagnostic cath will wait at least 4 hours for the PCI procedureACTPTT (lab)Whole BloodPTT (POC)5 min 15 minPCIEndTnT, CKMB, CK q8h x 3Immediately Post4 hoursPCIRoll-In andRoll-In andGroup IGroup I:Complete ReversalPartial Reversaland Sheath PullororGroup II:HeparinComplete ReversalSheath PullandSheath Pull14 daysEnd of Follow-upIndefiniteASAClopidogrelrecommend12 months
Page 1 and 2: Novel Anticoagulants andAntiplatele
Page 3 and 4: Targeting Blood Clotting Factors: I
Page 5 and 6: Common Adverse EventsAdverse events
Page 7: Apixaban: An Oral Direct Factor Xa
Page 11 and 12: Total major bleedingK-M estimated r

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