Betrixaban (PRT054021) is a non-vitamin K oral anticoagulant whose action is driven by the competitive and reversible inhibition of the factor Xa [1]. It was selected among all lead compounds due to its low hERG channel affinity while sustaining its factor Xa inhibition capacity [3]. Betrixaban, now developed by Portola Pharmaceuticals Inc., is prescribed as a venous thromboembolism (VTE) prophylactic for adult patients with moderate to severe restricted motility or with other risks for VTE [2]. VTE can be manifested as deep vein thrombosis or pulmonary embolism and it is a leading cause of preventable death in hospitalized patients [4].

Factor Xa
:1.5nM

在贴片钳制hERG实验中，Betrixaban的IC50为8.9 μM。Betrixaban对于血浆激肽释放酶的IC50和Ki值分别为6.3 μM和3.5 μM。相较于其他所有化合物(hERG Ki≤0.5 μM)，Betrixaban（hERG Ki为1.8 μM）展示了明显较低的hERG活性。

以0.5 mg/kg静脉注射（IV）和2.5 mg/kg口服（PO）给予Betrixaban时，其在狗的生物利用度为51.6%；以0.75 mg/kg IV和7.5 mg/kg PO给予时，其在猴子的生物利用度为58.7%[1]。Betrixaban和Apixaban引起的全血国际标准化比率（INR）增加可被r-Antidote类似地逆转。在单独给予三种fXa抑制剂（每种分别给予）静脉（i.v.）输注30分钟后，rivaroxaban、Betrixaban和apixaban的总血浆浓度分别为1.4±0.4 μM（平均值±标准差）、0.2±0.01 μM和1.4±0.3 μM，未结合抑制剂的百分比分别为2.2%±0.8%（平均值±标准差）、40%±7.2%和1.5%±0.3%。r-Antidote给药后，这些抑制剂的总血浆浓度分别上升至1.9±0.09 μM、2.0±0.4 μM和4.2±0.7 μM，未结合抑制剂的百分比分别下降到0%、0.3%±0.1%和0.05%±0.02%。因此，对于这三种抑制剂，r-Antidote纠正凝血酶原时间至接近正常值与抑制剂的自由部分减少相关联[2]。

To measure the inhibition of fXa activity by direct fXa inhibitors and the reversal of its inhibitory effect by r-Antidote, purified human plasma fXa (3 nM) (Haematologic Technologies), varying concentrations of inhibitor (0, 2.5, 5.0 and 7.5 nM) and r-Antidote are added to the assay buffer (20 mM Tris, 150 mM NaCl, 5 mM Ca2+ and 0.1% BSA, pH 7.4). After incubation at room temperature for 30 min, 100 μM Spectrozyme-fXa is added to the mixture, and the initial rate of sub?strate cleavage is monitored continuously for 5 min at 405 nm in a 96-well plate reader. The initial velocity of product formation as a function of inhibitor and r-Antidote concentrations is analyzed by Dynafit to estimate the binding affinity of r-Antidote to each inhibitor[2]. .

Whole-blood INR values (mean±s.d.) in rats infused with Betrixaban (1 mg/kg per hour) or vehicle and then treated with either vehicle or r-Antidote by i.v. bolus (6 mg) over 5 min plus infusion (9 mg/h) for up to 90 min. Circles, vehicle+vehicle; squares, Betrixaban + vehicle; triangles, Betrixaban + r-Antidote. *P≤0.02 compared to the r-Antidote treatment group determined by unpaired two-tailed t test. Whole-blood INR values (mean±s.d.) in rats infused with Apixaban (0.5 mg per kg body weight h?1) or vehicle and then treated with either vehicle or r-Antidote by i.v. bolus (6 mg) over 5 min plus infusion (6 mg/h) for up to 90 min. Circles, vehicle + vehicle; squares, apixaban + vehicle; triangles, apixaban+r-Antidote. *P≤0.01 compared to the r-Antidote treatment group determined by unpaired two-tailed t test.