Betrixaban

A highly potent, selective Factor Xa inhibitor with Ki/IC50 of 0.117 nM/1.5 nM; no significant activity against thrombin, plasmin, tPA, activated protein C, and kallikrein; exhibts weak binding affinity for hERG (Ki=0.42 uM) ; orally efficacious.Thrombosis Phase 3 Clinical (In Vitro) :Betrixaban (PRT054021) shows IC50 of 8.9 μM in patch clamp hERG assays.Betrixaban shows an IC50 and a Ki of 6.3 μM and 3.5 μM for the plasma kallikrein, respectively.Betrixaban (hERG Ki 1.8 μM) exhibits significantly lower hERG activity than all the others (hERG Ki 0.5 μM) .Betrixaban (5-25 ng/mL) inhibits thrombin generation. (In Vivo) :Betrixaban (0.5 mg/kg, i.v.; 2.5 mg/kg, p.o.) has oral bioavailability of 51.6% in dog.Betrixaban (0.75 mg/kg, i.v.; 7.5 mg/kg, p.o.) has oral bioavailability of 58.7% in monkey.Betrixaban mediated whole-blood INR increase is reversed by r-Antidote. After i.v. infusion for 30 min, the total plasma concentrations of Betrixaban is 0.2±0.01 μM, and the percentages of unbound inhibitor is 40%±7.2%. After administration of r-Antidote, the total plasma concentration increased to 2.0±0.4 μM, and the percentage of unbound inhibitor declined to 0.3%±0.1%.Betrixaban (3 mg/kg) shows nearly comparable inhibition of thrombus mass to enoxaparin 1.6 mg/kg (76% vs 96% inhibition) in the rabbit abdominal vena cava model of clot accretion on cotton threads.Betrixaban (19.1 mg/kg) is at least as effective at maintaining patency as enoxaparin 7.6 mg/kg and clopidogrel 3 mg/kg/d (90% vs 70% vs 80% patency, respectively) in the ferric chloride injury model of rodent carotid artery.