Thrombin (binds to both active site and exosite 1 of thrombin) [1]

In P2Y12+/+ arteries, bivalirudin (2 mg/kg) postponed the start of first thrombus and the time to occlusion, but neither treatment avoided vascular occlusion [2].

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In the Bivalirudin Angioplasty Trial (BAT) with 4312 patients undergoing coronary balloon angioplasty for unstable or postinfarction angina, bivalirudin significantly reduced the combined endpoint of death, myocardial infarction, or repeat revascularization at 7 days (odds ratio 0.78, 95% CI 0.62-0.99) and at 90 days (odds ratio 0.82, 95% CI 0.70-0.96); major bleeding events were significantly less frequent with bivalirudin (3.5%) than with unfractionated heparin (9.3%, p<0.001) [1].

In the REPLACE-2 trial with 6010 patients undergoing percutaneous coronary intervention, bivalirudin (0.75 mg/kg bolus, 1.75 mg/kg/h infusion during procedure) with provisional GPIIb/IIIa inhibitor use was noninferior to heparin plus planned GPIIb/IIIa inhibitor for the primary quadruple endpoint of death, myocardial infarction, urgent revascularization at 30 days and major in-hospital bleeding (9.2% vs 10.0%); there were significant reductions in major bleeding (2.4% vs 4.1%, p<0.001) and thrombocytopenia (0.7% vs 1.7%, p<0.001) with bivalirudin; at 12 months, mortality was 1.9% with bivalirudin vs 2.4% with heparin, with strong trends toward mortality reduction in high-risk subgroups including patients >75 years (3.6% vs 6.9%, p=0.04), diabetes (2.3% vs 3.9%, p=0.07), renal insufficiency (creatinine clearance <60 ml/min, 4.5% vs 7.1%, p=0.09), and unstable angina (1.4% vs 3.0%, p=0.02) [1].

In P2Y12-/- mice, bivalirudin (2 mg/kg) significantly inhibited thrombus volume on collagen-coated surfaces at 1700 s-1; in wild-type mice, bivalirudin had no significant effect on thrombus volume on collagen, but on tissue factor-coated surfaces at 871 s-1, bivalirudin significantly reduced thrombus volume in both wild-type and P2Y12-/- mice [2].

In an in vivo FeCl3-induced mesenteric artery injury model in mice, bivalirudin (2 mg/kg intravenous, 15 minutes before injury) delayed the time for first thrombus appearance and occlusion in P2Y12+/+ arteries but did not prevent vessel occlusion; in P2Y12+/- mice, bivalirudin abolished thrombus formation for approximately 40 minutes, after which the thrombotic process reappeared [2].

Mice (P2Y12+/+, P2Y12+/-, and P2Y12-/-) were infused with bivalirudin at 2 mg/kg intravenously 1 hour before ex vivo perfusion chamber experiments. Blood was collected from the vena cava of anesthetized mice and perfused directly through type III collagen-coated or tissue factor-coated capillary chambers (282 or 345 μm diameter for 1700 and 871 s-1, respectively) for 2.5 minutes [2].

For intravital microscopy, bivalirudin (2 mg/kg) was injected intravenously into mice 15 minutes before FeCl3-induced vessel wall injury. Rhodamine 6G (0.2 mg/mL) was administered through the tail vein 10 minutes before visualization of mesenteric arteries (shear rate 1000-1400 s-1). Vessel-wall injury was generated by a 2×1 mm filter paper saturated with 12.5% FeCl3 solution for 7 minutes, and platelet vessel-wall interactions were recorded for 40 additional minutes or until full occlusion occurred and lasted for more than 20 seconds [2].

Absorption, Distribution and Excretion
Following intravenous injection, bivalirudin exhibits linear pharmacokinetics. After a bolus injection of 1 mg/kg, continuous intravenous infusion at a rate of 2.5 mg/kg/hr over 4 hours resulted in a mean steady-state concentration of 12.3 ± 1.7 mcg/mL. Bivalirudin is primarily cleared from plasma via renal mechanisms (20%) and proteolytic activity. 0.2 L/kg
3.4 mL/min/kg [Normal Renal Function]
3.4 mL/min/kg [Mild Renal Insufficiency]
2.7 mL/min/kg [Moderate Renal Insufficiency]
2.8 mL/min/kg [Severe Renal Insufficiency]
1 mL/min/kg [Dialysis-Dependent Patient]

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Metabolism/Metabolites
80% Protein Hydrolysis

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Biological Half-Life
Normal Renal Function: 25 minutes (under normal conditions)
Cretin clearance 10-29 mL/min: 57 minutes
Dialysis-Dependent Patient: 3.5 hours

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Intravenous administration produces immediate anticoagulant effects that return to baseline approximately 1 to 2 hours after cessation of drug administration [1].

Bivalirudin exhibits linear pharmacokinetics with rapid plasma clearance (about 3 ml/min/kg) and a small volume of distribution (0.2 L/kg) [1].

The half-life of bivalirudin is approximately 25 minutes, with prolongation in patients with moderate (34 minutes) or severe (57 minutes) renal impairment (glomerular filtration rate 30-59 ml/min and <30 ml/min, respectively) [1].

The drug is degraded primarily by peptidases in the blood and degraded forms are cleared via the kidneys; only 20% of the active moiety is eliminated via the kidney [1].

Bivalirudin exhibits linear dose-proportional plasma concentration responses with a positive correlation between dose and anticoagulant effect (measured by activated clotting time and activated partial thromboplastin time) [1].

Effects During Pregnancy and Lactation
◉ Overview of Use During Lactation
There is currently no information regarding the use of bivalirudin during lactation. Since this drug is absorbed orally, alternative medications are recommended.
◉ 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
Except for thrombin and erythrocytes, bivalirudin does not bind to plasma proteins.

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Observed toxic effects for bivalirudin in acute-toxicity studies were generally related to the exaggerated pharmacodynamic effects of the drug [1].

No significant adverse effects on reproductive parameters in rats following subcutaneous administration of bivalirudin (up to 150 mg/kg/day); no potential for teratogenicity or mutagenicity; no potential for antigenic or immunogenic responses in test animals [1].

Bleeding complications are reduced compared with unfractionated heparin; bivalirudin is not associated with thrombocytopenia [1].

In the REPLACE-2 trial, bivalirudin significantly reduced major bleeding (2.4% vs 4.1%, p<0.001) and thrombocytopenia (0.7% vs 1.7%, p<0.001) compared to heparin plus GPIIb/IIIa inhibitors [1].

[1]. Bivalirudin: an anticoagulant option for percutaneous coronary intervention.Expert Rev Cardiovasc Ther. 2004 Mar;2(2):153-62.

[2]. Anticoagulants (thrombin inhibitors) and aspirin synergize with P2Y12 receptor antagonism in thrombosis.Circulation. 2003 Nov 25;108(21):2697-703.

Bivalirudin is a synthetic peptide composed of 20 amino acids, with the following amino acid sequence: D-Phe, Pro, Arg, Pro, Gly, Gly, Gly, Gly, Asn, Gly, Asp, Phe, Glu, Glu, Ile, Pro, Glu, Glu, Tyr, and Leu. It is a homologue of hirudin (a natural drug found in the saliva of medicinal leeches) and is a specific and reversible thrombin inhibitor used as an anticoagulant. It is both an anticoagulant and an EC 3.4.21.5 (thrombin) inhibitor. Bivalirudin is a synthetic peptide (thrombin inhibitor) composed of 20 amino acid residues that reversibly inhibits thrombin. Once bound to its active site, thrombin cannot activate fibrinogen to form fibrin, a key step in thrombosis. It is administered intravenously. Because bivalirudin can cause blood stasis, monitoring changes in hematocrit, activated partial thromboplastin time, international normalized ratio, and blood pressure is crucial. Bivalirudin is a synthetic peptide composed of 20 amino acids with thrombin-specific anticoagulant properties. Bivalirudin reversibly binds to the catalytic and anion-binding sites of thrombin (including free thrombin and thromboconjugated thrombin), thereby preventing the formation and activation of fibrin, factor XIIIa, and other coagulation factors. This drug is primarily used during coronary angioplasty and is often used in combination with aspirin for patients with unstable angina. Bivalirudin trifluoroacetate is the trifluoroacetate form of bivalirudin, a synthetic peptide composed of 20 amino acids with thrombin-specific anticoagulant activity. After intravenous injection, bivalirudin reversibly binds to the catalytic and anion-binding sites of thrombin (including free thrombin and thromboconjugated thrombin), thereby preventing the formation and activation of fibrin, factor XIIIa, and other coagulation factors. Bivalirudin is primarily used during coronary angioplasty and is often used in combination with aspirin for patients with unstable angina. Drug Indications For the treatment of heparin-induced thrombocytopenia and prevention of thrombosis. Bivalirudin is indicated for patients undergoing percutaneous coronary intervention (PCI) and for patients with moderate to high-risk acute coronary syndrome due to unstable angina or non-ST-segment elevation myocardial infarction who are scheduled for PCI. FDA Label Angiox is indicated for adult patients undergoing percutaneous coronary intervention (PCI), including patients with ST-segment elevation myocardial infarction (STEMI) undergoing emergency PCI. Angiox is also indicated for adult patients with unstable angina/non-ST-segment elevation myocardial infarction (UA/NSTEMI) who are scheduled for emergency or early intervention. Angiox should be used in combination with aspirin and clopidogrel. Treatment of Atherosclerosis and Thrombosis Mechanism of Action Inhibits thrombin activity by binding to the catalytic and anion-binding sites of thrombin. Thrombin is a serine protease that plays a central role in thrombus formation. It cleaves fibrinogen into fibrin monomers and activates factor XIII to factor XIIIa, enabling fibrin to form a covalently cross-linked framework, thereby stabilizing the thrombus. Thrombin also activates factors V and VIII, promoting further thrombin production and activating platelets, stimulating their aggregation and particle release.

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Pharmacodynamics
Bivalirudin exerts its inhibitory effect on thrombin by directly and specifically binding to the catalytic and anion-binding sites of circulating and thrombus-binding thrombin. The effect of bivalirudin is reversible because thrombin slowly cleaves the thrombin-bivalirudin bond, thereby restoring the active site of thrombin.

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Bivalirudin is a 20 amino acid synthetic peptide designed from hirudin; it binds to thrombin with high affinity, forming a bivalirudin/thrombin complex; once bound, thrombin cleaves the prolyl-arginyl bond at the amino-terminal of bivalirudin, resulting in recovery of thrombin active-site function; the reversibility of the bivalirudin/thrombin complex relative to the hirudin/thrombin complex provides a safety advantage [1].

Bivalirudin was approved in 2000 by the US FDA as an anticoagulant in patients with unstable angina undergoing percutaneous coronary intervention [1].

Bivalirudin does not require antithrombin as a cofactor, has a predictable anticoagulant response because it does not bind to any plasma proteins other than thrombin, inhibits both fluid-phase and fibrin-bound thrombin, inhibits thrombin-mediated platelet activation, and retains activity in the presence of platelet-rich thrombi because it is not inhibited by platelet factor 4 [1].

In the REPLACE-2 trial, bivalirudin reduced in-hospital costs by approximately $400 per patient compared to unfractionated heparin plus GPIIb/IIIa inhibitors, primarily attributable to reductions in major bleeding and thrombocytopenia [1].

Bivalirudin with provisional GPIIb/IIIa use provides protection from ischemic events comparable to unfractionated heparin plus planned GPIIb/IIIa use but with significantly fewer bleeding complications and less thrombocytopenia [1].

In mouse models, bivalirudin synergizes with P2Y12 antagonism to inhibit thrombosis; thrombin inhibition combined with P2Y12 deficiency abolished thrombus formation in P2Y12+/- mice, demonstrating a strong synergistic antithrombotic effect [2].

C100H139F3N24O35

2294.3402

2179.989

128270-60-0

Bivalirudin TFA;1191386-55-6

16129704

White to off-white solid powder

1.5±0.1 g/cm3

1.675

-2.24

28

35

67

155

4950

16

CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC3=CC=CC=C3)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@@H]4CCCN4C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]5CCCN5C(=O)[C@@H](CC6=CC=CC=C6)N

OIRCOABEOLEUMC-GEJPAHFPSA-N

InChI=1S/C98H138N24O33/c1-5-52(4)82(96(153)122-39-15-23-70(122)92(149)114-60(30-34-79(134)135)85(142)111-59(29-33-78(132)133)86(143)116-64(43-55-24-26-56(123)27-25-55)89(146)118-67(97(154)155)40-51(2)3)119-87(144)61(31-35-80(136)137)112-84(141)58(28-32-77(130)131)113-88(145)63(42-54-18-10-7-11-19-54)117-90(147)66(45-81(138)139)110-76(129)50-107-83(140)65(44-71(100)124)109-75(128)49-106-73(126)47-104-72(125)46-105-74(127)48-108-91(148)68-21-13-38-121(68)95(152)62(20-12-36-103-98(101)102)115-93(150)69-22-14-37-120(69)94(151)57(99)41-53-16-8-6-9-17-53/h6-11,16-19,24-27,51-52,57-70,82,123H,5,12-15,20-23,28-50,99H2,1-4H3,(H2,100,124)(H,104,125)(H,105,127)(H,106,126)(H,107,140)(H,108,148)(H,109,128)(H,110,129)(H,111,142)(H,112,141)(H,113,145)(H,114,149)(H,115,150)(H,116,143)(H,117,147)(H,118,146)(H,119,144)(H,130,131)(H,132,133)(H,134,135)(H,136,137)(H,138,139)(H,154,155)(H4,101,102,103)/t52-,57+,58-,59-,60-,61-,62-,63-,64-,65-,66-,67-,68-,69-,70-,82-/m0/s1

H-D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu-OH

Bivalirudin Trifluoroacetate; BG-8967; BG8967; BG 8967; Brand name: Angiomax Angiox.

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)

H2O : ~10 mg/mL (~4.59 mM)

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*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.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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