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 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].

Absorption, Distribution and Excretion
Betrixaban presents a rapid absorption at a dose of 80 mg. Its peak plasma concentration is registered within 3-4 hours after oral administration in healthy humans. The oral bioavailability is 34%, and it can be reduced with the consumption of food. Specifically, the Cmax and AUC is reduced by an average of 70% and 61% with a low-fat meal, and 50% and 48% with a high-fat meal compared to the fasted state, an effect which is apparent up to six hours following food intake.
Betrixaban is reported to present mainly a gastrointestinal elimination route, it has been shown that even 85% of it gets disposed in the feces and only 11% of it can be found in the urine.
The apparent volume of distribution os 32 L/kg.
Betrixaban presents a minimal renal clearance (being 5-7% of the administered dose).

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Metabolism / Metabolites
One of the major characteristics of Betrixaban is its minimal hepatic metabolism (< 1%), preventing potential accumulation with liver impariment. Unchanged Betrixaban is the main form found in human plasma, followed by two hydolitic CYP-independent inactive metabolites (15-18%). The minimal hepatic metabolism produces an unlikely drug-to-drug interaction with inhibitors or agonists of CYP450.

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Biological Half-Life
Betrixaban presents a long half-life of between 19-27 hours.

Hepatotoxicity
In registration studies, serum aminotransferase elevations of greater than 3 times the upper limit of normal (ULN) occurred in 1% to 2% of betrixaban-treated patients and in a similar proportion of control subjects treated with enoxaparin. Similarly, aminotransferase levels rose to above 5 times ULN in 0.6% of betrixaban and 0.4% of enoxaparin treated control subjects. Aminotransferase elevations with jaundice arose in
Likelihood score: E* (unproven but suspected rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Betrixaban is no longer marketed in the United States. Because no information is available on the use of betrixaban during breastfeeding and the drug is orally absorbable, an alternate drug is preferred, especially while nursing a newborn or preterm infant.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Betrixaban is reported to be present a proteing binding of about 60%.

[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.

Betrixaban is a secondary carboxamide obtained by formal condensation of the carboxy group of 4-(N,N-dimethylcarbamimidoyl)benzoic acid with the amino group of 2-amino-N-(5-chloropyridin-2-yl)-5-methoxybenzamide. A synthetic anticoagulant compound that targets activated factor Xa in the coagulation cascade. It has a role as an anticoagulant and an EC 3.4.21.6 (coagulation factor Xa) inhibitor. It is a member of guanidines, a member of benzamides, a secondary carboxamide, a monochloropyridine and a monomethoxybenzene.
Betrixaban is a non-vitamin K oral anticoagulant whose action is driven by the competitive and reversible inhibition of the factor Xa. It was selected among all lead compounds due to its low hERG channel affinity while sustaining its factor Xa inhibition capacity. 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. VTE can be manifested as deep vein thrombosis or pulmonary embolism and it is a leading cause of preventable death in hospitalized patients.
Betrixaban is a Factor Xa Inhibitor. The mechanism of action of betrixaban is as a Factor Xa Inhibitor.
Betrixaban is an oral anticoagulant and direct inhibitor of factor Xa which is used to decrease the risk of deep vein thrombosis and pulmonary embolus in patients hospitalized with an acute medical condition who are at high risk for venous thromboses. Betrixaban has been linked to a low rate of serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent liver injury.
Betrixaban is an orally active inhibitor of coagulation factor Xa (activated factor X) with anticoagulant activity. Betrixaban is primarily excreted unchanged in the bile and has a half life of about 19 hours.

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Drug Indication
Betrixaban is indicated for prophylaxis of venous thromboembolism (VTE) in conditions of moderate to severe restricted mobility or in patients that qualify as in risk of VTE.
FDA Label
Prevention of venous thromboembolism
Prevention of venous thromboembolism

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Mechanism of Action
Betrixaban is a cofactor-independent direct inhibitor of the Factor Xa and inhibits free and prothrombinase-bound Factor Xa.

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Pharmacodynamics
Betrixaban is an oral anticoagulant that excerts its action by preventing thrombin generation without having a direct effect on platelet aggregation.

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.)