In patch clamp hERG tests, betrixaban (PRT054021) exhibits an IC50 of 8.9 μM[1]. Betrixaban exhibits an IC50 and a Ki for plasma kallikrein of 6.3 μM and 3.5 μM, respectively[1]. Compared to all other drugs (hERG Ki⩽0.5 μM), betrixaban (hERG Ki 1.8 μM) shows noticeably less hERG activity[1]. Betrixaban inhibits the production of thrombin (5–25 ng/mL)[3].

In patch clamp hERG tests, betrixaban (PRT054021) exhibits an IC50 of 8.9 μM[1]. Betrixaban exhibits an IC50 and a Ki for plasma kallikrein of 6.3 μM and 3.5 μM, respectively[1]. Compared to all other drugs (hERG Ki⩽0.5 μM), betrixaban (hERG Ki 1.8 μM) shows noticeably less hERG activity[1]. Betrixaban inhibits the production of thrombin (5–25 ng/mL)[3].

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In a whole blood prothrombinase inhibition assay, Betrixaban showed dose-dependent inhibition of platelet-mediated prothrombinase activity, consistent with its mechanism of action as a direct FXa inhibitor.
In a tissue factor-induced thrombin generation assay, Betrixaban at concentrations ranging from 5 ng/mL to 25 ng/mL inhibited thrombin generation to a degree comparable to the trough and peak levels achieved by fondaparinux 2.5 mg.
Preclinical toxicology studies using patch clamp assays showed that Betrixaban was not a potent inhibitor of the hERG potassium channel (IC50 = 8.9 μM). The ratio of hERG IC50 to the expected peak plasma concentration in humans provided a 30-fold safety margin against significant hERG channel inhibition. [3]

In dogs, betrixaban has an oral bioavailability of 51.6% (0.5 mg/kg, iv; 2.5 mg/kg, po)[1]. In monkeys, betrixaban has an oral bioavailability of 58.7% (0.75 mg/kg, iv; 7.5 mg/kg, po)[1]. R-Antidote reverses the whole-blood INR rise mediated by betrixaban. Following a 30-minute IV infusion, the overall plasma concentration of betrixaban is 0.2±0.01 μM, with 40%±7.2% of the inhibitor remaining unbound. Following r-Antidote delivery, the fraction of unbound inhibitor decreased to 0.3%±0.1% while the overall plasma concentration rose to 2.0±0.4 μM[2]. When used in the rabbit abdominal vena cava model of clot accretion on cotton threads, betrixaban (3 mg/kg) exhibits almost equal inhibition of thrombus mass to enoxaparin 1.6 mg/kg (76% vs. 96% inhibition)[3]. In the ferric chloride damage model of the rat carotid artery, betrixaban (19.1 mg/kg) is at least as effective as enoxaparin 7.6 mg/kg and clopidogrel 3 mg/kg/d (90% vs. 70% vs. 80% patency, respectively) at maintaining patency[3].

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In a rabbit abdominal vena cava model of clot accretion, Betrixaban at a dose of 3 mg/kg showed nearly comparable inhibition of thrombus mass (76% inhibition) to enoxaparin 1.6 mg/kg (96% inhibition).
In a ferric chloride injury model of rodent carotid artery, Betrixaban at 19.1 mg/kg was at least as effective as enoxaparin 7.6 mg/kg and clopidogrel 3 mg/kg/day in maintaining arterial patency (90% vs. 70% vs. 80% patency, respectively).
In a baboon arteriovenous (AV) shunt thrombosis model, Betrixaban demonstrated dose-dependent inhibition of radiolabeled platelet deposition at both venous and arterial sides. Doses ranging from 0.05 mg/kg to 0.49 mg/kg produced plasma concentrations of 7–83 ng/mL and resulted in 30%–90% inhibition of platelet deposition at the venous side of the shunt. [3]

The anticoagulant effect and mechanism of Betrixaban were evaluated using in vitro coagulation assays. In whole blood, its ability to inhibit prothrombinase activity (the complex that converts prothrombin to thrombin) was measured, showing dose-dependent inhibition.
A tissue factor-induced thrombin generation assay was performed in plasma. Betrixaban was added at specified concentrations (5–25 ng/mL), and the inhibition of thrombin generation over time was measured and compared to the effect of a standard dose of fondaparinux.
The inhibitory constant (Ki) and half-maximal inhibitory concentration (IC50) for Factor Xa were determined using enzymatic assays with the recombinant enzyme. Betrixaban demonstrated potent and selective inhibition of FXa. [3]

1 mg/kg; oral
Rats

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The antithrombotic efficacy of Betrixaban was evaluated in three animal models. In the rabbit abdominal vena cava model, thrombus formation was induced on cotton threads, and drugs were administered intravenously. In the rodent ferric chloride carotid artery injury model, thrombosis was induced by topical application of ferric chloride, and drugs were administered. In the baboon AV shunt model, an external shunt was placed between the femoral artery and vein, and platelet deposition was monitored using radiolabeled platelets after intravenous drug administration. Specific drug formulation details were not provided. [3]

Absorption, Distribution and Excretion
Bectraxaban is rapidly absorbed at an 80 mg dose. Peak plasma concentrations are reached within 3–4 hours after oral administration in healthy individuals. Oral bioavailability is 34%, which decreases with food intake. Specifically, compared to a fasting state, Cmax and AUC are reduced by an average of 70% and 61% after a low-fat meal, and by 50% and 48%, respectively, after a high-fat meal. This effect remains significant up to 6 hours after food intake. Bectraxaban is reported to be primarily excreted via the gastrointestinal tract; studies have shown that up to 85% of bectraxaban is excreted in feces, with only 11% excreted in urine. The apparent volume of distribution is 32 L/kg. The renal clearance of bectraxaban is extremely low (only 5–7% of the administered dose). Metabolism/Metabolites One of the key characteristics of bectraxaban is its extremely low hepatic metabolism (<1%), thus avoiding drug accumulation that may occur in cases of hepatic impairment. In human plasma, the unchanged betracitabine is the predominant form, followed by two inactive metabolites independent of CYP hydrolases (15-18%). Due to minimal hepatic metabolism, drug interactions with CYP450 inhibitors or agonists are unlikely.

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Biological Half-Life
Btraxaban has a relatively long half-life, ranging from 19 to 27 hours.

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In healthy volunteers, after oral administration of 80 mg betracitabine, btraxaban is rapidly absorbed, reaching peak plasma concentration (Tmax) within 3-4 hours.
Oral bioavailability is 34%. Concurrent intake of fatty foods reduces peak concentration (Cmax) and area under the curve (AUC) by approximately 50%.
Approximately 60% of betracitabine is bound to plasma proteins.
Btraxaban is primarily excreted unchanged in the feces via the hepatobiliary route (82%–89% of the administered dose), possibly mediated by the P-glycoprotein (P-gp) efflux pump. Renal clearance is extremely low, accounting for only 5%–7% of the oral dose. Bectroxaban is minimally metabolized in the liver by cytochrome P450 (CYP450) enzymes (<1%) and does not induce or inhibit CYP450. The terminal elimination half-life (t1/2) is 37 hours. The effective half-life of bectroxaban (the time required for its anticoagulant effect to decrease by 50%) is approximately 20 hours. The plasma peak-to-trough concentration ratio of bectroxaban is low. [3]

Hepatotoxicity
In the registration study, 1% to 2% of patients treated with betraxaban experienced serum transaminase levels exceeding 3 times the upper limit of normal (ULN), a similar proportion was observed in the control group treated with enoxaparin. Similarly, 0.6% of the control group treated with betraxaban experienced transaminase levels exceeding 5 times the ULN, and 0.4% of the control group treated with enoxaparin experienced this. Probability score: E (Unproven but suspected rare cause of clinically significant liver injury). Use during pregnancy and lactation ◉ Overview of use during lactation
Btraxaban has been discontinued in the United States. Since there is currently no information regarding the use of betraxaban during lactation, and the drug is orally absorbed, alternative medications are recommended, especially for breastfed newborns or preterm infants. ◉ Effects on breastfed infants
As of the revision date, no relevant published information was found.
◉ Effects on Lactation and Breast Milk
As of the revision date, no relevant published information was found.

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Protein Binding
Betradix baniform has been reported to have a protein binding rate of approximately 60%.

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The main toxic risk of anticoagulants is bleeding. In the Phase II clinical trial, the incidence of clinically relevant bleeding was lower in the betroxaban group than in the control group (enoxaparin or warfarin). In the EXPLORE-Xa trial, the incidence of gastrointestinal adverse events (including diarrhea, nausea, dyspepsia, and vomiting) was higher in the betroxaban group (especially the 80 mg dose group) compared to warfarin. Most adverse events were mild. No significant signs of hepatotoxicity were observed. In the Phase II study, the incidence of elevated alanine aminotransferase (>3 times the upper limit of normal) was no higher in the betroxaban group than in the control group, and the elevation was transient. No cases of elevated bilirubin were reported. Although betraxaban is derived from a class of compounds with hERG channel inhibitory potential, comprehensive QTc interval studies in healthy volunteers and ECG monitoring in clinical trials have shown that betraxaban (up to a single dose of 140 mg) does not cause clinically significant QTc interval prolongation exceeding regulatory thresholds. As a substrate for P-gp, co-administration with potent P-gp inhibitors (such as ketoconazole) can increase plasma concentrations of betraxaban by approximately two-fold. [3]

[1]. Discovery of Betrixaban (PRT054021), N-(5-chloropyridin-2-yl)-2-(4-(N,N-dimethylcarbamimidoyl)benzamido)-5-methoxybenzamide, a highly potent, selective, and orally efficacious factor Xa inhibitor. Bioorg Med Chem Lett. 2009 Apr 15;19(8):21.

[2]. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat Med. 2013 Apr;19(4):446-51.

[3]. Profile of betrixaban and its potential in the prevention and treatment of venous thromboembolism. Vasc Health Risk Manag. 2015 Jun 26;11:343-51.

Bectrazaban is a secondary amide compound formed by the condensation of the carboxyl group of 4-(N,N-dimethylcarbamoylimino)benzoic acid and the amino group of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide. It is a synthetic anticoagulant that targets factor Xa, the activating factor in the coagulation cascade. It is both an anticoagulant and an EC 3.4.21.6 (coagulation factor Xa) inhibitor. It belongs to the guanidine, benzamide, secondary amide, monochloropyridine, and monomethoxybenzene classes. Bectrazaban is a non-vitamin K antagonist oral anticoagulant whose mechanism of action is through competitive and reversible inhibition of factor Xa. Its low affinity for hERG channels while maintaining its factor Xa inhibitory ability has made it stand out among all lead compounds. Betrixaban, currently developed by Portola Pharmaceuticals Inc., is used to prevent VTE in adult patients with moderate to severe activity limitations or other risks of venous thromboembolism (VTE). VTE, which can manifest as deep vein thrombosis or pulmonary embolism, is one of the leading causes of preventable death in hospitalized patients. Betrixaban is a factor Xa inhibitor. Its mechanism of action is as a factor Xa inhibitor. Betrixaban is an oral anticoagulant and a direct inhibitor of factor Xa, used to reduce the risk of deep vein thrombosis and pulmonary embolism in patients hospitalized for acute illness at high risk of venous thrombosis. Betrixaban is associated with a lower incidence of elevated serum transaminases during treatment, but has not been found to be associated with clinically significant liver injury. Betrixaban is an orally effective inhibitor of coagulation factor Xa (activating factor X) with anticoagulant activity. Betrixaban is primarily excreted unchanged in bile, with a half-life of approximately 19 hours.

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Drug Indications
Bectroxaban is indicated for the prevention of VTE in patients with moderate to severe activity limitations or those meeting the risk criteria for venous thromboembolism (VTE).

FDA Label

Prevention of Venous Thromboembolism

Prevention of Venous Thromboembolism

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Mechanism of Action
Bectroxaban is a cofactor-independent direct inhibitor of factor Xa, inhibiting both free and prothrombin-bound factor Xa.Pharmacodynamics
Bectroxaban is an oral anticoagulant whose mechanism of action is through the inhibition of thrombin production without directly affecting platelet aggregation.Bectroxaban is an oral, direct, and selective factor Xa (FXa) inhibitor.
Its most notable pharmacological characteristics are minimal renal excretion, minimal hepatic metabolism via CYP450, and a long half-life (approximately 37 hours).
It has been evaluated in a phase II clinical trial for the prevention of venous thromboembolism after total knee arthroplasty (EXPERT trial) and for the prevention of stroke in patients with atrial fibrillation (EXPLORE-Xa trial).
A phase III clinical trial (APEX) is currently underway to evaluate the efficacy of long-term betraxaban (80 mg once daily for 35–42 days) versus short-term enoxaparin in the prevention of venous thromboembolism in high-risk patients with acute severe medical conditions.
Betraxaban is expected to be used in patients with severe renal insufficiency (creatinine clearance <30 mL/min), who are typically excluded from trials of other novel oral anticoagulants (NOACs).
There is currently no approved antidote. Btraxaban. Its long half-life may pose problems in cases of bleeding or requiring emergency surgery, however, an antidote (andasanetine α) is currently under joint development. [3]

C23H22CLN5O3

451.91

451.141

330942-05-7

Betrixaban-d6;2098655-51-5;Betrixaban maleate;936539-80-9;Betrixaban hydrochloride;2099719-47-6

10275777

Light yellow to yellow solid powder

1.3±0.1 g/cm3

200-212 ºC

1.629

2.93

3

5

7

32

668

0

XHOLNRLADUSQLD-UHFFFAOYSA-N

InChI=1S/C23H22ClN5O3/c1-29(2)21(25)14-4-6-15(7-5-14)22(30)27-19-10-9-17(32-3)12-18(19)23(31)28-20-11-8-16(24)13-26-20/h4-13,25H,1-3H3,(H,27,30)(H,26,28,31)

N-(5-Chloropyridin-2-yl)-2-((4-(N,N-dimethylcarbamimidoyl)benzoyl)amino)-5- methoxybenzamide

PRT054021; PRT-021; MK-4448; MLN-1021; PRT 054021; PRT-054021; MK4448; MLN 1021; PRT 021; PRT021; MK 4448; MLN1021; trade name Bevyxxa

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (5.53 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)