Factor Xa (FXa)

Human plasma PT, TT, and APTT are prolonged by edoxaban tosylate in a concentration-dependent manner (1, 1, and 5 minutes, respectively) [1]. With an IC50 of 2.90 µM, edoxaban tosylate suppresses platelet aggregation induced by thrombin[1].

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Inhibitory effect of Edoxaban/DU‐176b on FXa Inhibition of human FXa by DU‐176b was concentration‐dependent and competitive, as shown by the Lineweaver–Burk plot (Fig. 2). The Ki value was 0.561 nm (Table 1), a marked improvement in potency compared with DX‐9065a (Ki = 41 nm) [6]. DU‐176b also inhibited cynomolgus monkey and rabbit FXa with similar potency, whereas the Ki for rat FXa was higher than that for human FXa (Table 1), similar to the profile of DX‐9065a. For FXa bound to FVa, Ca2+ and phospholipids within the prothrombinase complex using S‐2222 as a substrate, inhibition by DU‐176b was competitive (Fig. 3A). The Ki value was 0.903 nm, comparable to its inhibition of free FXa. DU‐176b also suppressed the generation of thrombin from prothrombin by prothrombinase in a non‐competitive/mixed‐type of inhibition (Fig. 3B), with a 5.3‐fold higher Ki (2.98 nm) than that obtained with free FXa.

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Specificity of Edoxaban/DU‐176b DU‐176b was a weak inhibitor of thrombin and FIXa, with Ki values of 6.00 and 41.7 μm, respectively; more than 10 000‐fold higher than the Ki for FXa. There was no effect on the activities of FVIIa/sTF, FXIa, tPA, aPC, trypsin, plasmin and chymotrypsin, demonstrating the high specificity of DU‐176b for FXa.

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Anticoagulant activity in vitro PT, APTT and TT of human plasma were prolonged by Edoxaban/DU‐176b in a concentration‐dependent manner, doubling PT and APTT at 0.256 and 0.508 μm, respectively (Table 2). The CT2 for TT, however, was much higher (4.95 μm), reflecting its anti‐thrombin activity as shown in the enzyme inhibition assay. The potency of DU‐176b for PT prolongation was similar in human, cynomolgus monkey and rabbit plasma, whereas a higher concentration was needed in rat plasma.

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Effects on human platelet aggregation in vitro Edoxaban/DU‐176b did not impair human platelet aggregation induced by ADP, collagen or U46619 (a thromboxane A2 receptor agonist) at concentrations of up to 100 μm in PRP. Thrombin‐induced platelet aggregation was inhibited by a high concentration of DU‐176b (IC50: 2.90 μm), reflecting its weak anti‐thrombin activity.

Edoxaban tosylate (0.5, 2.5, and 12.5 mg/kg; oral; once) prolongs prothrombin time (PT) and decreases thrombosis in a significant and dose-dependent manner [1].

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PD and PK studies in rats and monkeys [1]
There was significant FXa inhibition activity in plasma (86% and 94% inhibition) in rats 0.5 h after oral administration of Edoxaban/DU‐176b (2.5 and 5 mg kg−1) (Fig. 4A), which was sustained for up to 4 h. In cynomolgus monkeys, DU‐176b also elicited a rapid onset of anti‐FXa activity, reaching a peak at 4 h (93%) and persisting 24 h (11%) after dosing (Fig. 4B). The area under the curve (AUC) of plasma concentration and maximum concentration (Cmax) after 1 mg kg−1 DU‐176b dosing were 852 ± 284 ng·h mL−1 and 175 ± 74 ng mL−1 (n = 6, mean ± standard deviation). Compared with DU‐176b, DX‐9065a had a lower anti‐FXa potency in both species (Fig. 4). AUC and Cmax in cynomolgus monkeys after the 1 mg kg−1 DX‐9065a dosing were 191 ± 104 ng·h mL−1 and 36.8 ± 20.5 ng mL−1 (n = 6).

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Antithrombotic effects of orally administered Edoxaban/DU‐176b [1]
Venous stasis thrombosis model in rats and rabbits Infusion of hypotonic saline and stasis of the inferior vena cava in rats led to the formation of thrombi weighing 4.38 ± 0.53 mg. Oral administration of DU‐176b (0.5, 2.5 and 12.5 mg kg−1) significantly and dose‐dependently reduced the thrombus formation (Fig. 5A) and prolonged PT (Fig. 5B). The plasma samples derived from DU‐176b‐treated rats inhibited exogenous FXa activity (Fig. 5C). In rabbits, DU‐176b also exerted a dose‐dependent antithrombotic effect (Fig. 5D), PT prolongation, and anti‐FXa activity in plasma (data not shown), significantly decreasing thrombi by 91% at 3 mg kg−1.

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Platinum wire‐induced venous thrombosis model [1]
Placement of a platinum wire in the rat vein induced formation of thrombi weighing 2.45 ± 0.38 mg on the surface of the wire. The thrombus formation was significantly reduced by Edoxaban/DU‐176b in a dose‐dependent manner (Fig. 6A). At a dose of 2.5 mg kg−1, DU‐176b reduced thrombus formation to 0.73 ± 0.21 mg. Similarly, FXa inhibition activity in plasma was significant and dose‐dependent (Fig. 6B).

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Effect on bleeding time [1]
Effect of Edoxaban/DU‐176b on tail bleeding time was not significantly different from control at 3 mg kg−1 (Table 3). At higher doses (10 and 30 mg kg−1), bleeding time was significantly prolonged (1.9‐fold) compared with the control.

Anti‐FXa activity of Edoxaban/DU‐176b [1]
To determine the inhibitory effect of DU‐176b on FXa activity, FXa was added to the mixture of DU‐176b or 5% dimethylsulfoxide (DMSO) control and a chromogenic substrate S‐2222 (250–1000 μm) in a reaction buffer (20 mm Tris–HCl, pH 7.4, 150 mm NaCl, 0.1% BSA). The final concentrations of FXa were as follows: human FXa (0.005 U mL−1, 0.7 nm), rabbit FXa (0.005 U mL−1, molarity unavailable), rat FXa (0.025 U mL−1, 10 nm) and cynomolgus monkey FXa (0.025 U mL−1, 3 nm). To measure amidolysis of S‐2222 by FXa, the absorbance at 405 nm was monitored with a microplate spectrophotometer SPECTRAmax 340 (Molecular Devices, Sunnyvale, CA, USA) at 30 °C for 10 min and the reaction velocity (mO.D./min) was obtained. The inhibition constant (Ki) values of DU‐176b were calculated by the Lineweaver–Burk plots and subsequent secondary plots.

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Inhibition of prothrombinase by Edoxaban/DU‐176b [1]
The inhibitory effect of DU‐176b on prothrombinase activity was examined using S‐2222 and the physiological substrate prothrombin, as described by Rezaie. Briefly, lipid vesicles were prepared by mixing of 1.2 mm phosphatidylcholine and 0.4 mm phosphatidylserine in chloroform, drying under vacuum, and resuspending in 9% sucrose. The suspension was sonicated and vesicles were extruded through filters of pore size 50–200 nm. Prothrombinase was formed by mixing human FXa (0.4 nm for S‐2222 and 0.2 pm for prothrombin), FVa (10 nm), CaCl2 (2.5 mm), and phosphatidylcholine/phosphatidylserine vesicles (25 μm) at 37 °C for 5 min. Amidolysis of S‐2222 (250–1000 μm) was measured as described for anti‐FXa activity of DU‐176b. Thrombin generation from prothrombin (7.8–250 nm) was measured as follows: the prothrombinase reaction proceeded for 3 min and was stopped by the addition of 10 mm EDTA. The activity of generated thrombin was measured by the amidolysis of its substrate S‐2238 and the concentration of thrombin was determined from a standard curve. The Ki values were calculated using the Lineweaver‐Burk plots and subsequent secondary plots.

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Specificity of serine protease inhibition of Edoxaban/DU‐176b [1]
The effects of DU‐176b on the following serine proteases (final concentrations) were examined: thrombin (0.03 U mL−1, 0.5 nm), FVIIa/sTF (2 nm/20 nm), FIXa (6.25 U mL−1, molarity unavailable), FXIa (0.25 nm), tPA (750 U mL−1, 20 nm), aPC (2.5 nm), trypsin (0.3 U mL−1, 1 nm), plasmin (0.004 U mL−1, 4 nm), and chymotrypsin (0.005 U mL−1, 2.5 nm). The enzymatic activities were assessed by the amidolysis of the following chromogenic substrates for correspondent protease: S‐2238 for thrombin, Spectrozyme fVIIa for FVIIa/sTF, Spectrozyme fIXa for FIXa, S‐2366 for FXIa and aPC, S‐2288 for tPA, S‐2251 for plasmin, S‐2222 for trypsin, and S‐2586 for chymotrypsin. The Ki values for these enzymes were determined as previously described.

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Anticoagulant activity in vitro [1]
The in vitro anticoagulant effects of Edoxaban/DU‐176b were studied. Clotting time (CT) in human, rat, cynomolgus monkey and rabbit plasma was measured using a microcoagulometer Amelung KC‐10A (MC Medical, Tokyo, Japan) and anticoagulant activity was expressed as the concentration of DU‐176b required to double CT (CT2), estimated by regression analysis from the dose‐response curves. Prothrombin time (PT) was measured by incubating plasma and DU‐176b (control; 4% DMSO/saline) for 1 min at 37 °C, followed by the addition of Thromboplastin C Plus (final concentration 0.25 U mL−1). Activated partial thromboplastin time (APTT) was measured by incubating plasma, DU‐176b and Platelin LS for 5 min at 37 °C, followed by the addition of CaCl2 (8.3 mm). Thrombin time (TT) was measured by incubating plasma and DU‐176b for 1 min at 37 °C, followed by the addition of human thrombin (4 U mL−1).

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Platelet aggregation [1]
Platelet‐rich plasma (PRP) was prepared from blood samples of healthy volunteers by centrifugation at 200 × g for 10 min at room temperature. To prepare washed platelets, PRP was then centrifuged at 600 × g for 10 min and the pellet was washed three times in Cor buffer (138 mm NaCl, 2.9 mm KCl, 10 mm Hepes‐NaOH, pH 7.3, 5.5 mm glucose, 12 mm NaHCO3) containing prostaglandin E1 (1 μm) and EDTA (10 mm). Washed platelets (2 × 108 platelets mL−1) were suspended in Cor buffer containing fibrinogen (1 mg mL−1) and CaCl2 (1 mm). EdoxabanDU‐176b was added to PRP or washed platelet suspension and incubated for 2 or 4 min at 37 °C. Platelet aggregation (>60%) was induced by the addition of collagen (0.8 μg mL−1), U46619 (0.7 μm) or ADP (5 μm) in PRP, and thrombin (0.08 U mL−1) in washed platelet suspension. Platelet aggregation was measured using an aggregometer PAM‐12C (MC Medical). Regression analysis was used to calculate the IC50 of DU‐176b.

Cell viability assay [1]
Cell Types: human, rat, cynomolgus monkey, rabbit plasma; human platelet
Tested Concentrations:
Incubation Duration: 1 and 5 minutes
Experimental Results: Antithrombin.

Animal/Disease Models: Male Slc: Wistar rat (210-240g); male New Zealand white rabbit (2.5-3.5kg) (both are venous stasis and thrombosis models) [1].
Doses: 0.5, 2.5 and 12.5 mg/kg
Route of Administration: Oral; Primary
Experimental Results:Inhibition of exogenous FXa activity. Anti-thrombotic.

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PD and PK studies of Edoxaban/DU‐176b after oral administration to rats and cynomolgus monkeys [1]
DU‐176b, DX‐9065a or the 0.5% methylcellulose vehicle were administered orally to fasted animals by gavage, and citrated blood samples were collected at 0.5, 1, 2 and 4 h in rats (n = 4 per dose group), and 0.5, 1, 2, 4, 8 and 24 h in cynomolgus monkeys (n = 6 per dose group) after administration. To measure FXa inhibition activity in plasma, a plasma sample (5 μL) was added to the reaction mixture of human FXa (0.01 U mL−1, 1.4 nm) and S‐2222 (300 μm). Amidolysis of S‐2222 was measured as described. The plasma concentrations of DU‐176b and DX‐9065a were measured by high‐performance liquid chromatography with tandem mass spectrometric detection.

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Antithrombotic effects of orally administered Edoxaban/DU‐176b [1]
Venous stasis thrombosis model in rats DU‐176b (0.5–12.5 mg kg−1) or 0.5% methylcellulose was orally administered to fasted rats (n = 8 per dose group). Venous thrombosis was induced 30 min after DU‐176b administration according to the method by Hladovec while the animals were anesthetized with thiopental sodium (100 mg kg−1, i.p.). Briefly, hypotonic NaCl solution (0.225%) was injected into the femoral vein (5 mL kg−1 min−1 for 2 min), and the inferior vena cava was ligated just below the left renal vein. Ten minutes later, the vena cava was ligated again 1.5 cm below the first ligature. The resulting thrombus was removed 1 h after the second ligation and its wet weight was measured. Blood samples were collected 29 min after DU‐176b dosing to measure PT and plasma FXa inhibition activity.

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Venous stasis thrombosis model in rabbits [1]
DU‐176b/Edoxaban (0.3–3 mg kg−1) or 0.5% methylcellulose was administered orally to fasted rabbits (n = 8 per dose group). The rabbits were anesthetized with urethane (2 g kg−1, i.p.) and venous thrombosis was induced 45 min after DU‐176b administration according to the method by Wessler et al. with some modifications. Recombinant human TF (0.05 μg 2‐mL−1 kg−1 for 30 s) was injected into the auricular vein, and 15 s later blood stasis was made in a 2‐cm segment of the jugular vein by a pair of ligations. The resulting thrombus was removed after 30 min, and its wet weight was measured.

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Platinum wire‐induced venous thrombosis model in rats [1]
Thrombus was induced by the insertion of a platinum wire (2 cm long) into the inferior vena cava of rats (n = 8 per dose group) just caudal to the left renal vein 30 min after oral administration of Edoxaban/DU‐176b (0.1–2.5 mg kg−1) or 0.5% methylcellulose according to the method of Lavelle and Iomhair. The resulting thrombus was fixed 1 h later with 1% glutaraldehyde. The wet weight of the thrombus was measured and blood samples were collected 29 min after DU‐176b dosing to measure plasma FXa inhibition activity.

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Effect of Edoxaban/DU‐176b on bleeding time [1]
Hemorrhage was induced 30 min following oral administration of DU‐176b (3–30 mg kg−1) or 0.5% methylcellulose and bleeding time was measured in a rat tail bleeding model. Briefly, an incision (1 mm deep) was made 4 cm from the tip of the tail. Blood was blotted every 15 s on filter papers, and bleeding time was defined as the time from the incision to the first arrest of bleeding. The maximum observation period was 30 min and longer bleeding time was assigned a value of 30 min.

Absorption, Distribution and Excretion
Following oral administration, peak plasma concentrations of edoxaban occur within 1–2 hours. Absolute bioavailability is 62%. Edoxaban is primarily excreted unchanged in the urine. Renal clearance (11 L/h) accounts for approximately 50% of the total edoxaban clearance (22 L/h). Metabolism and bile/intestinal excretion account for the remaining clearance. Steady-state volume of distribution is 10⁷ L. 22 L/h / Milk / There are currently no data on the presence of edoxaban in human milk… Edoxaban has been detected in rat milk… The drug distribution is biphasic. Steady-state volume of distribution (Vdss) is 10⁷ (19.9) L (mean (standard deviation)). In vitro plasma protein binding is approximately 55%. No clinically significant edoxaban accumulation was observed with once-daily administration (accumulation ratio 1.14).
Crushing 60 mg tablets and mixing them into applesauce or dissolving them in water, then administering via nasogastric tube, results in drug exposure similar to that of whole tablets.
Eduxaban is primarily excreted unchanged in the urine. Renal clearance (11 L/h) accounts for approximately 50% of the total edoxaban clearance (22 L/h). Metabolism and bile/intestinal excretion account for the remaining clearance.
Peak plasma edoxaban concentrations are reached within 1–2 hours after oral administration. The absolute bioavailability is 62%. Food does not affect systemic exposure to edoxaban. In the ENGAGE AF-TIMI 48 and Hokusai VTE trials, Savaysa can be taken with or without food.
Metabolism/Metabolites
Eduxaban is primarily metabolized via CYP3A4, therefore drug interactions are minimal. However, it interacts with drugs that inhibit P-glycoprotein (P-gp), which is responsible for transporting edoxaban across the intestinal wall. Edoxaban exists primarily in its parent form in plasma. Edoxaban is metabolized mainly by hydrolysis (mediated by carboxylesterase 1), conjugation, and CYP3A4 oxidation, but to a very low degree. The major metabolite M-4, produced by hydrolysis, is human-specific and active, with exposure in healthy subjects less than 10% of the parent compound. Exposure to other metabolites is less than 5% of edoxaban exposure. All subjects received a single oral dose of 60 mg edoxaban in Phase 1, and in Phase 2, on day 7, received a single oral dose of 60 mg edoxaban and 600 mg rifampin (2 300 mg capsules once daily) for 7 days. A 6-day washout period was provided between the two treatment phases. Plasma concentrations of edoxaban and its metabolites M4 and M6 were measured, and limited assessments of coagulation pharmacodynamics were performed. A total of 34 healthy subjects were included, of whom 32 completed the study. Rifampin in combination with edoxaban reduced edoxaban exposure but increased exposure to its active metabolites. Rifampin increased the apparent oral clearance of edoxaban by 33% and shortened its half-life by 50%. At early time points, the anticoagulant effect based on prothrombin time (PT) and activated partial thromboplastin time (aPTT), with or without rifampin, remained above expected levels and higher than with edoxaban alone, likely due to the increased contribution of the active metabolites. Edoxaban was well tolerated in this healthy adult population. Rifampin reduced edoxaban exposure while increasing exposure to its active metabolites M4 and M6. PT and aPTT values did not change significantly at early time points. However, these data should be interpreted with caution.
Edoxaban and its low-abundance active metabolite M4 are substrates of P-glycoprotein (P-gp; MDR1) and organic anion transporter 1B1 (OATP1B1), respectively. Pharmacological inhibitors of P-gp and OATP1B1 affect the pharmacokinetics (PK) of edoxaban and M4. In this integrated pharmacogenomics analysis, we summarized genotype and concentration-time data from 458 healthy volunteers in 14 completed phase I studies to investigate the impact of allele variations in ABCB1 (rs1045642: C3435T) and SLCO1B1 (rs4149056: T521C) encoding P-gp and OATP1B1 on edoxaban PK parameters. Although certain pharmacological inhibitors of P-gp and OATP1B1 increase edoxaban exposure, neither the ABCB1 C3435T nor the SLCO1B1 T521C polymorphisms affect the pharmacokinetics of edoxaban. A slightly elevated M4 exposure was observed in carriers of the SLCO1B1 C allele; however, this elevation is unlikely to be clinically significant, as plasma M4 concentrations account for <10% of total edoxaban concentrations. The major metabolite M-4, produced by hydrolysis, is human-specific and active, with exposure in healthy subjects less than 10% of the parent compound. Exposure to other metabolites is less than 5% of edoxaban exposure. The dominant form in plasma is unmetabolized edoxaban. Edoxaban is metabolized primarily through hydrolysis (mediated by carboxylesterase 1), conjugation, and CYP3A4 oxidation, with very low metabolic rates.
Biological Half-Life
The terminal elimination half-life of orally administered edoxaban is 10 to 14 hours.

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
Since there is currently no information regarding the use of edoxaban during lactation, and this drug is orally absorbed, alternative medications are recommended, especially when breastfeeding newborns or premature infants.
◉ Effects on Breastfed Infants
No published information found as of the revision date.
◉ Effects on Breastfeeding and Breast Milk
No published information found as of the revision date. Toxicity Overview Identification and Uses: Edoxaban is a white to pale yellow-white crystalline powder. It is used to reduce the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. This product is also used to treat deep vein thrombosis (DVT) and pulmonary embolism that occur after 5 to 10 days of initial parenteral anticoagulant therapy. Human Studies: Overdose increases the risk of bleeding. Edoxaban increases the risk of bleeding and may cause serious or even fatal bleeding. If any bleeding occurs during treatment, the patient should be evaluated immediately. If active pathological bleeding occurs, medication should be discontinued. However, minor or “annoying” bleeding is common in patients receiving any anticoagulant therapy and should not be a reason to discontinue treatment. In vitro human lymphocyte micronucleus assays showed that edoxaban and its human-specific metabolite M-4 are not genotoxic. Animal studies: Edoxaban was administered daily by gavage to mice and rats for up to 104 weeks without carcinogenicity. At doses up to 1000 mg/kg/day, edoxaban had no effect on fertility or early embryonic development in rats. In a rat prenatal and postnatal developmental study, edoxaban was administered orally at doses up to 30 mg/kg/day during organogenesis and on day 20 of lactation. At a dose of 30 mg/kg/day, vaginal bleeding was observed in pregnant rats, and delayed avoidance responses (learning test) were observed in female offspring. Embryo-fetal development studies were conducted in pregnant rats and rabbits during organogenesis. In rats, no malformations were observed with oral administration of edoxaban at doses up to 300 mg/kg/day. At 300 mg/kg/day, post-implantation embryo loss was increased, but this effect may be due to maternal vaginal bleeding in rats at this dose. In rabbits, no malformations were observed at doses up to 600 mg/kg/day. Embryo-fetal toxicity was observed at maternally toxic doses, including absence or smaller fetal gallbladders at 600 mg/kg/day, and increased post-implantation embryo loss, increased spontaneous abortion, and reduced live birth count and fetal weight at doses equal to or greater than 200 mg/kg/day. Edoxaban and its human-specific metabolite M-4 showed genotoxicity in in vitro chromosomal aberration assays, but no genotoxicity was observed in in vitro bacterial reverse mutation assays (Ames test), in vivo rat bone marrow micronucleus assay, in vivo rat liver micronucleus assay, and in vivo unplanned DNA synthesis assay.

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Hepatotoxicity
Among patients treated with edoxaban, 2% to 5% experience serum transaminase elevations exceeding three times the upper limit of normal. This rate is similar to or lower than in the warfarin or control groups. These elevations are usually transient and without symptoms or jaundice. No clinically significant liver injury cases were reported in premarketing studies, but experience with a large number of patients treated long-term is lacking. In large healthcare databases, the incidence of liver injury with edoxaban is slightly lower than with rivaroxaban and apixaban, but the number of patients treated with edoxaban is limited, and the nature of liver injury is not described.
Probability score: D (Clinically significant liver injury is likely due to racial factors).

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Pregnancy and Lactation Effects
◉ Overview of Use During Lactation
Since there is currently no information on the use of edoxaban during lactation, and the drug is orally absorbed, alternative medications are recommended, especially for breastfed newborns or premature infants.
◉ Effects on breastfed infants
No published information found as of the revision date.
◉ Effects on lactation and breast milk
No published information found as of the revision date.

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Protein binding
In vitro plasma protein binding is approximately 55%.

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Interactions
Edoxaban is an oral direct factor Xa inhibitor currently under development for thrombosis prevention, including the prevention of stroke and systemic embolism in patients with atrial fibrillation (AF). P-glycoprotein (P-gp) is an efflux transporter that regulates the absorption and excretion of exogenous substances. Edoxaban is a substrate of P-gp, and some cardiovascular (CV) drugs have the potential to inhibit P-gp and increase drug exposure. The aim of this study was to evaluate the potential pharmacokinetic interactions between edoxaban and six cardiovascular drugs used to treat atrial fibrillation, as well as known P-gp substrates/inhibitors. Drug interaction studies of edoxaban with cardiovascular drugs known to have P-gp substrate/inhibitor potential were conducted in healthy subjects. In four crossover, two-cycle, two-group treatment studies, subjects received 60 mg edoxaban as monotherapy, or in combination with 300 mg quinidine (n = 42), 240 mg verapamil (n = 34), 80 mg atorvastatin (n = 32), or 400 mg dronedarone (n = 34), respectively. Furthermore, the efficacy of 60 mg edoxaban monotherapy and in combination with 400 mg amiodarone (n = 30) or 0.25 mg digoxin (n = 48) was evaluated in a single-sequence study and a two-cohort study, respectively. When edoxaban was used in combination with quinidine (76.7%), verapamil (52.7%), amiodarone (39.8%), and dronedarone (84.5%), edoxaban exposure, measured by area under the curve, increased; when used in combination with quinidine (11.8%), verapamil (29.1%), and dronedarone (157.6%), edoxaban exposure, measured by 24-hour concentration, also increased. Concomitant use of edoxaban with amiodarone reduced edoxaban 24-hour concentration by 25.7%. Concomitant use with digoxin or atorvastatin had minimal effect on edoxaban exposure. Concomitant use with the P-gp inhibitors quinidine, verapamil, and dronedarone increased edoxaban exposure. Amiodarone, atorvastatin, and digoxin had small/minimal effects.
Eduxaban, an oral direct factor Xa inhibitor, is a substrate of P-glycoprotein (P-gp) and is metabolized by carboxylesterase-1 and cytochrome P450 (CYP)3A4/5. A single-dose edoxaban study investigated the effects of rifampin-induced P-gp and CYP3A4/5 expression on the transport and metabolism of edoxaban via the CYP3A4/5 pathway. This was a phase I, open-label, two-treatment, two-cycle, single-sequence drug interaction study conducted in healthy adults. All subjects received a single oral dose of 60 mg edoxaban in phase I and a 7-day course of rifampin treatment (2 300 mg capsules once daily) in phase II, with a single oral dose of 60 mg edoxaban on day 7. A 6-day washout period was included between the two treatment phases. Plasma concentrations of edoxaban and its metabolites M4 and M6 were measured, and limited assessments of coagulation pharmacodynamics were performed. A total of 34 healthy subjects were enrolled, of whom 32 completed the study. Rifampin, when used in combination with edoxaban, reduced edoxaban exposure but increased exposure to its active metabolites. Rifampin increased the apparent oral clearance of edoxaban by 33% and shortened its half-life by 50%. At early time points, anticoagulant activity based on prothrombin time (PT) and activated partial thromboplastin time (aPTT), with or without rifampin, remained above expected levels and higher than with edoxaban alone, likely due to the increased contribution of the active metabolites. Edoxaban was well tolerated in this healthy adult population. Rifampin reduced edoxaban exposure while increasing exposure to its active metabolites M4 and M6. PT and aPTT values at early time points did not change significantly; however, these data should be interpreted with caution. Verapamil increased peak plasma concentrations and systemic exposure of edoxaban by approximately 53%; pharmacokinetic parameters of verapamil were only slightly altered. In patients with venous thromboembolism, the dose of edoxaban should be reduced when used concomitantly with verapamil. Quinidine increases peak plasma concentration and systemic exposure of edoxaban by approximately 85% and 77%, respectively, but edoxaban does not affect the pharmacokinetics of quinidine. In patients with venous thromboembolism, the dose of edoxaban should be reduced when used concomitantly with quinidine. For more complete data on drug interactions of edoxaban (19 items in total), please visit the HSDB record page.

[1]. DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J Thromb Haemost. 2008 Sep;6(9):1542-9.

Eduxaban tosylate hydrate is a monohydrate of edoxaban tosylate. It is used to treat deep vein thrombosis (DVT) and pulmonary embolism. It has anticoagulant, EC 3.4.21.6 (coagulation factor Xa) inhibitor, and platelet aggregation inhibitory effects. It contains edoxaban tosylate.

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Drug Indications
For the prevention of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (NVAF) and one or more of the following risk factors: congestive heart failure, hypertension, age ≥75 years, diabetes, history of stroke or transient ischemic attack (TIA)
For the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) in adults, and for the prevention of recurrent DVT and PE.

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Eduxaban tosylate is an organic sulfonate composed of equimolar amounts of edoxaban and 4-tosylate. It (in monohydrate form) is used to treat deep vein thrombosis and pulmonary embolism. It has anticoagulant, EC 3.4.21.6 (coagulation factor Xa) inhibitor, and platelet aggregation inhibitor effects. It contains edoxaban (1+). Edoxaban tosylate is the tosylate form of edoxaban, an orally effective factor Xa (activating factor X) inhibitor with anticoagulant activity. Edoxaban is administered in the form of edoxaban tosylate. The elimination half-life of this drug is 9-11 hours, and it is primarily excreted via the kidneys. Edoxaban tosylate is a small molecule drug with clinical trials up to Phase IV (covering all indications). It was first approved in 2015 and currently has 5 approved indications and 1 investigational indication. This drug carries an FDA black box warning.

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Therapeutic Use
Xa Factor Inhibitors
/Clinical Trials/ ClinicalTrials.gov is a registry and results database that lists human clinical studies funded by public and private institutions worldwide. The website is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each record on ClinicalTrials.gov includes a summary of the study protocol, including: the disease or condition; the intervention (e.g., the medical product, behavior, or procedure under investigation); the title, description, and design of the study; participation requirements (eligibility criteria); the location of the study; contact information for the study location; and links to relevant information from other health websites, such as the NLM's MedlinePlus (which provides patient health information) and PubMed (which provides citations and abstracts of academic articles in the medical field). The database contains edoxaban.
Savaysa is indicated for reducing the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF). /Included on US Product Label/
Savaysa is indicated for the treatment of deep vein thrombosis (DVT) and pulmonary embolism (PE) after 5 to 10 days of initial parenteral anticoagulation therapy. /Included on US Product Label/
For more complete data on the therapeutic uses of edoxaban (out of 7), please visit the HSDB record page.

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Drug Warning
/Black Box Warning/ Efficacy is reduced in patients with nonvalvular atrial fibrillation whose creatinine clearance (CrCL) > 95 mL/min. Savaysa should not be used in patients with CrCL > 95 mL/min. In the ENGAGE AF-TIMI 48 study, the incidence of ischemic stroke was increased in patients with nonvalvular atrial fibrillation whose CrCL > 95 mL/min was treated with warfarin. For these patients, an alternative anticoagulant should be used.
/Black Box Warning/ Premature discontinuation of Savaysa increases the risk of ischemic events. Premature discontinuation of any oral anticoagulant in the absence of adequate alternative anticoagulation therapy increases the risk of ischemic events. If Savaysa is discontinued for reasons other than pathological bleeding or completion of treatment, consider using an alternative anticoagulant as directed in the transition guidelines.
/Warning/ Spinal/Epidural Hematoma. Epidural or spinal hematomas may occur in patients receiving Savaysa and undergoing spinal anesthesia or spinal puncture. These hematomas can lead to long-term or permanent paralysis. These risks should be considered when scheduling patients for spinal surgery. Factors that may increase the risk of epidural or spinal hematoma in these patients include: use of an indwelling epidural catheter; concurrent use of other medications that affect hemostasis, such as nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, or other anticoagulants; a history of traumatic or recurrent epidural or spinal punctures; a history of spinal deformity or spinal surgery; and the unknown optimal time interval between Savaysa administration and spinal procedures. Patients should be closely monitored for signs and symptoms of neurological dysfunction. If neurological impairment is found, emergency treatment is necessary. For patients currently receiving or about to receive anticoagulation therapy, the benefits and risks should be weighed before spinal intervention. The safety and efficacy of edoxaban in patients undergoing mechanical heart valve replacement or with moderate to severe mitral stenosis have not been evaluated; its use is not recommended in such patients. For more complete data on edoxaban (18 of these), please visit the HSDB records page. Pharmacodynamics: Edoxaban can prolong coagulation time test results, such as activated partial thromboplastin time (aPTT), prothrombin time (PT), and international normalized ratio (INR). Edoxaban is a monocarboxylic acid amide (in its tosylate monohydrate form) used to treat deep vein thrombosis and pulmonary embolism. It has anticoagulant, EC 3.4.21.6 (coagulation factor Xa) inhibitor, and platelet aggregation inhibitory effects. It is a monocarboxylic acid amide, chloropyridine, thiazopyridine, and tertiary amine compound. It is the conjugate base of edoxaban (1+). Edoxaban belongs to the class of novel oral anticoagulants (NOACs) and is a rapid-acting, oral, selective factor Xa inhibitor. Edoxaban inhibits the stepwise amplification of factor Xa, a key protein in the coagulation cascade, preventing thrombosis. It is indicated for reducing the risk of stroke and systemic embolism (SE) in patients with nonvalvular atrial fibrillation (NVAF), and for treating deep vein thrombosis (DVT) and pulmonary embolism (PE) after 5-10 days of initial parenteral anticoagulation therapy. Traditionally, warfarin (a vitamin K antagonist) has been used to prevent stroke in this population, but its effective use has been limited by its slow onset of action, narrow therapeutic window, need for regular monitoring and INR testing, and various drug-drug and drug-food interactions. This has led to considerable interest in novel drugs such as dabigatran, apixaban, and rivaroxaban, which are believed to be effective in preventing thrombosis. In addition to once-daily dosing, these drugs offer advantages over warfarin, including a significantly reduced risk of hemorrhagic stroke and gastrointestinal bleeding, as well as improved patient adherence, which is crucial for many patients requiring lifelong treatment. Edoxaban is a factor Xa inhibitor. Edoxaban's mechanism of action is as a factor Xa inhibitor. Edoxaban is an oral small-molecule factor Xa inhibitor used as an anticoagulant to reduce the risk of venous thrombosis, systemic embolism, and stroke in patients with atrial fibrillation, and is used to treat deep vein thrombosis and pulmonary embolism. The incidence of elevated serum transaminases during edoxaban treatment is low, and clinically significant acute liver injury is rare. Edoxaban is an orally effective inhibitor of coagulation factor Xa (activating factor X) with anticoagulant activity. Edoxaban is administered in the form of edoxaban tosylate. The elimination half-life of this drug is 9-11 hours, and it is primarily excreted by the kidneys.
Eduxaban is a small molecule drug that has completed Phase IV clinical trials (covering all indications) and was first approved in 2015. It has 6 approved indications and 15 investigational indications. This drug has received a black box warning from the U.S. Food and Drug Administration (FDA).

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Background: Factor Xa (FXa) is a key serine protease that converts prothrombin to thrombin in the coagulation cascade and is a promising target enzyme for the prevention and treatment of thromboembolic diseases. Edoxaban/DU-176b is a novel antithrombotic drug that directly inhibits FXa activity.
Objective: To evaluate the in vitro pharmacological properties and in vivo effects of DU-176b in animal models of thrombosis and hemorrhage.
Methods: In vitro FXa inhibitory activity, specificity, and anticoagulant activity were assessed. Oral absorption was studied in rats and cynomolgus monkeys. In vivo effects were studied in rat and rabbit models of venous thrombosis and tail hemorrhage. Results: DU-176b/edoxaban showed a Ki value of 0.561 nM for free FXa and 2.98 nM for prothrombinase, exhibiting a selectivity for FXa exceeding 10,000-fold. In human plasma, DU-176b concentrations of 0.256 μM and 0.508 μM both doubled prothrombin time and activated partial thromboplastin time. DU-176b did not affect ADP, collagen, or U46619-induced platelet aggregation. DU-176b was well absorbed in rats and monkeys, and its anti-Xa activity was stronger after oral administration, with plasma drug concentrations higher than the original FXa inhibitor DX-9065a. In vivo experiments showed that DU-176b inhibited thrombus formation in rat and rabbit thrombosis models in a dose-dependent manner, although bleeding time in rats was not significantly prolonged at antithrombotic doses. Conclusion: Compared with the prototype drug DX-9065a, DU-176b/edoxaban is a more potent and selective FXa inhibitor with higher oral bioavailability. DU-176b is a promising new anticoagulant for the prevention and treatment of thromboembolic diseases. [1] In summary, edoxaban/DU-176b is a potent and highly selective direct FXa inhibitor with significantly improved potency, selectivity and oral bioavailability compared with DX-9065a. This study shows that DU-176b has the potential as an oral antithrombotic drug and is a promising new anticoagulant for the prevention and treatment of thromboembolic diseases. [1]

C₃₁H₃₈CLN₇O₇S₂

720.26

719.196

C, 51.70; H, 5.32; Cl, 4.92; N, 13.61; O, 15.55; S, 8.90

480449-71-6

Edoxaban;480449-70-5;Edoxaban tosylate monohydrate;1229194-11-9;Edoxaban hydrochloride;480448-29-1

25022378

White to off-white solid powder

4.404

5

12

6

49

1090

3

CC1=CC=C(C=C1)S(=O)(=O)O.CN1CCC2=C(C1)SC(=N2)C(=O)N[C@@H]3C[C@H](CC[C@@H]3NC(=O)C(=O)NC4=NC=C(C=C4)Cl)C(=O)N(C)C

ZLFZITWZOYXXAW-QXXZOGQOSA-N

InChI=1S/C24H30ClN7O4S.C7H8O3S/c1-31(2)24(36)13-4-6-15(27-20(33)21(34)30-19-7-5-14(25)11-26-19)17(10-13)28-22(35)23-29-16-8-9-32(3)12-18(16)37-23;1-6-2-4-7(5-3-6)11(8,9)10/h5,7,11,13,15,17H,4,6,8-10,12H2,1-3H3,(H,27,33)(H,28,35)(H,26,30,34);2-5H,1H3,(H,8,9,10)/t13-,15-,17+;/m0./s1

N'-(5-chloropyridin-2-yl)-N-[(1S,2R,4S)-4-(dimethylcarbamoyl)-2-[(5-methyl-6,7-dihydro-4H-[1,3]thiazolo[5,4-c]pyridine-2-carbonyl)amino]cyclohexyl]oxamide;4-methylbenzenesulfonic acid

DU-176b; DU 176; DU176; Edoxaban tosylate; 480449-71-6; Edoxaban tosilate; DU 176-b; edoxaban monotosylate; UNII-32W99UE810; CHEBI:85975; edoxaban p-toluenesulfonate; DU-176b; DU-176; Edoxaban; Savaysa; Lixiana

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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

DMSO : ~50 mg/mL (~69.42 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (3.47 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 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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Solubility in Formulation 2: ≥ 2.5 mg/mL (3.47 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (3.47 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (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 900 μL of corn oil and mix evenly.

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