Eptifibatide is a cyclic heptapeptide with antiplatelet properties that functions as a competitive antagonist of activated platelet glycoprotein IIb/IIIa receptors [1].

Absorption, Distribution and Excretion
55 mL/kg/h [patients with coronary artery disease]
/MILK/ It is not known whether eptifibatide is distributed into milk in humans.
Eptifibatide is approximately 25% bound to plasma proteins, principally (9-16%) to albumin.The volume of distribution of eptifibatide in patients with coronary artery disease is about 185-260 mL/kg and is somewhat higher (220-270 mL/kg) in healthy individuals.
Eptifibatide, a synthetic peptide inhibitor of the platelet glycoprotein IIb/IIIa receptor, has been studied as an antithrombotic agent in a variety of acute ischemic coronary syndromes. The purpose of the present study was to characterize the disposition of (14)C-eptifibatide in man after a single intravenous (i.v.) bolus dose. (14)C-Eptifibatide (approximately 50 uCi) was administered to eight healthy men as a single 135-ug/kg IV bolus. Blood, breath carbon dioxide, urine, and fecal samples were collected for up to 72 hours postdose and analyzed for radioactivity by liquid scintillation spectrometry. Plasma and urine samples were also assayed by liquid chromatography with mass spectrometry for eptifibatide and deamidated eptifibatide (DE). Mean (+/- SD) peak plasma eptifibatide concentrations of 879 +/- 251 ng/mL were achieved at the first sampling time (5 minutes), and concentrations then generally declined biexponentially, with a mean distribution half-life of 5 +/- 2.5 minutes and a mean terminal elimination half-life of 1.13 +/- 0.17 hours. Plasma eptifibatide concentrations and radioactivity declined in parallel, with most of the radioactivity (82.4%) attributed to eptifibatide. A total of approximately 73% of administered radioactivity was recovered in the 72-hour period following (14)C-eptifibatide dosing. The primary route of elimination was urinary (98% of the total recovered radioactivity), whereas fecal (1.5%) and breath (0.8%) excretion was small. Eptifibatide is cleared by both renal and nonrenal mechanisms, with renal clearance accounting for approximately 40% of total body clearance. Within the first 24 hours, the drug is primarily excreted in the urine as unmodified eptifibatide (34%), DE (19%), and more polar metabolites (13%).
Plasma clearance of eptifibatide is proportional to body weight and estimated creatinine clearance and inversely proportional to age. Following a single IV dose of (14)C-radiolabeled eptifibatide (135 ug/kg) in healthy men, renal clearance averaged approximately 40-50% of total body clearance. Clearance is reduced by 50% in patients with moderate to severe renal impairment (estimated Clcr less than 50 mL/minute). Total body clearance in geriatric patients with coronary artery disease is lower than that in younger adults.
For more Absorption, Distribution and Excretion (Complete) data for Eptifibatide (9 total), please visit the HSDB record page.

---

Metabolism / Metabolites
No major metabolites have been detected in human plasma. Deamidated eptifibatide and other, more polar metabolites have been detected in urine.
(14)C-eptifibatide was extensively metabolized to deamidated eptifibatide and to several polar metabolites by both rats and monkeys. The drug-derived radioactivity excreted into the bile by rats, and identified as deamidated eptifibatide, was reabsorbed from the intestinal tract and further metabolized to more polar metabolites. The plasma and urine metabolite profiles in rats and monkeys indicate that the metabolic disposition of eptifibatide is similar for the two species.
Eptifibatide is metabolized principally through deamidation to a metabolite that has approximately 41% of the platelet-aggregation inhibitory activity of the parent compound, and through formation of other more polar metabolites. Approximately 27% of a dose of eptifibatide is broken down in plasma into naturally occurring amino acids; no major non-amino acid metabolites have been detected in plasma in humans.

---

Biological Half-Life
Approximately 2.5 hours
In Cynomolgus monkeys, plasma concentrations of (14)C-eptifibatide-derived radioactivity declined with a half life of about 12 hours following a single 2 mg/kg IV dose of (14)C-eptifibatide. Unchanged eptifibatide, which accounted for approximately 93% of total plasma (14)C at 5 min post-dose, was eliminated rapidly with a half life of 17 min.
In rats, plasma concentrations of (14)C-eptifibatide-derived radioactivity declined rapidly with a terminal phase half life of about 5 hours following a single 2 mg/kg IV dose of the radiolabeled drug. Unchanged eptifibatide declined with an apparent half life of about 8 min. Following single 2 and 20 mg/kg IV doses, the plasma concentrations of eptifibatide were dose-proportional and the half life (11 to 12 min) was dose-independent, indicating linear kinetics within the 2 to 20 mg/kg dose range.
The half-life of eptifibatide in patients with coronary artery disease averages 2.5-2.8 hours. In healthy individuals, half-life of the drug reportedly averages 0.83-2.4 hours.
... The purpose of the present study was to characterize the disposition of (14)C-eptifibatide in man after a single intravenous (IV) bolus dose. (14)C-Eptifibatide (approximately 50 uCi) was administered to eight healthy men as a single 135-ug/kg IV bolus. ... Mean (+/- SD) peak plasma eptifibatide concentrations of 879 +/- 251 ng/mL were achieved at the first sampling time (5 minutes), and concentrations then generally declined biexponentially, with a mean distribution half-life of 5 +/- 2.5 minutes and a mean terminal elimination half-life of 1.13 +/- 0.17 hours. ...

Toxicity Summary
IDENTIFICATION AND USE: Eptifibatide, as the drug Integrilin, is indicated to decrease the rate of a combined endpoint of death, new myocardial infarction (MI), or need for urgent intervention in patients undergoing percutaneous coronary intervention (PCI), including those undergoing intracoronary stenting. HUMAN EXPOSURE AND TOXICITY: Limited information is available on the acute toxicity of eptifibatide. In general, overdosage of eptifibatide in humans may be expected to produce effects that are extensions of the pharmacologic effects of the drug, predominantly bleeding. There have been cases of eptifibatide associated thrombocytopenia, which reinforces the importance of platelet count monitoring after therapy with this agent. Eptifibatide was not genotoxic in the human lymphocyte chromosome aberrations test. ANIMAL STUDIES: Single dose toxicity studies were conducted in rats, rabbits and monkeys; doses up to 500 ug/kg/minute administered by continuous intravenous infusion for 90 minutes did not cause mortality and were well-tolerated by all species. In rabbits, a dose-dependent decrease in platelet counts of the 50 and 500 ug/kg/minute (for 90 minutes)-dosed females was attributed to administration of eptifibatide. Findings in the monkeys were limited to petechial hemorrhages in the femoral and/or abdominal regions, which lasted for one to three days. Three out of five monkeys died or were sacrificed during the study due to contusions, excessive bleeding and/or petechial hemorrhages, which resulted in anemia. Total protein albumin and globulin values were reduced in all monkeys. At necropsy, focal hemorrhages in various organs were observed. In a fertility study in rats, dosing with eptifibatide had no effect on the course of pregnancy. No evidence of fertility or parental toxicity nor effects upon parental reproductive performance were observed at daily doses up to 72.0 mg/kg (24 times the maximum recommended daily human dose). Eptifibatide was not genotoxic in the Ames assay at doses up to 667 ug/mL, in the mouse lymphoma cell forward mutation assay at doses up to 1,000 ug/mL, or in the mouse micronucleus test.

---

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No published information is available on the use of eptifibatide during breastfeeding. Because eptifibatide is a peptide, absorption by the infant is unlikely because it is probably destroyed in the infant's gastrointestinal tract. Until more data become available, eptifibatide should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. If it is used by a nursing mother, monitor the infant for bruising and bleeding.
◉ 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.

---

Protein Binding
Approximately 25%

---

Interactions
Concomitant use of platelet-aggregation inhibitors and an anticoagulant (particularly in high dosages) may increase the risk of hemorrhage, and careful monitoring for bleeding is necessary, especially at arterial puncture sites. Eptifibatide and concomitant heparin therapy should be discontinued immediately and appropriate therapy (e.g., protamine sulfate in patients receiving heparin) instituted as necessary if serious bleeding occurs (e.g., bleeding not controlled by pressure). In healthy individuals, enoxaparin sodium (1 mg/kg subcutaneously every 12 hours for 4 doses) did not alter the pharmacokinetics or pharmacodynamics (platelet aggregation) of eptifibatide. The manufacturer states that caution should be employed when using eptifibatide with oral anticoagulants.
Eptifibatide has been administered concomitantly with thrombolytic agents (e.g., alteplase, streptokinase, tenecteplase) in a limited number of patients with acute myocardial infarction to reduce the risk of reocclusion of the infarct-related artery. Some clinicians suggest that use of short-acting platelet-aggregation inhibitors such as eptifibatide concomitantly with thrombolytic therapy may provide optimal benefit while minimizing the risk of bleeding However, use after thrombolysis of drugs that affect platelet function may increase the risk of bleeding complications, including those requiring blood transfusions, associated with thrombolytic therapy and has not been shown to be unequivocally effective to date; therefore, use of eptifibatide with thrombolytic therapy should be considered investigational and should be undertaken with caution.
Limited data from preclinical and clinical studies in patients receiving eptifibatide (0.5 mcg/kg per minute by IV infusion) alone or concomitantly with aspirin, heparin, or both drugs suggest no substantial pharmacokinetic or pharmacodynamic interactions (e.g., additive effects on platelet-aggregation inhibition) between eptifibatide and aspirin. While coadministration of eptifibatide and aspirin resulted in up to a fivefold increase in bleeding time compared with baseline values, similar increases in bleeding time were observed with aspirin and placebo. Nevertheless, since eptifibatide inhibits platelet aggregation, caution should be observed when the drug is used with other drugs that affect hemostasis, including thrombolytic agents, oral anticoagulants, nonsteroidal anti-inflammatory agents (NSAIAs), or dipyridamole. However, clopidogrel or ticlopidine was used routinely with eptifibatide in a large clinical, multicenter study (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT)) in patients undergoing coronary artery stent placement. To minimize potentially additive pharmacologic effects, the manufacturer of eptifibatide states that concomitant therapy with other platelet glycoprotein (GP IIb/IIIa)-receptor inhibitors (e.g., abciximab, tirofiban) should be avoided.

[1]. Platelet glycoprotein IIb/IIIa inhibitors in percutaneous coronary intervention: focus on the pharmacokinetic-pharmacodynamic relationships of eptifibatide. Clin Pharmacokinet. 2003;42(8):703-20.

Eptifibatide is a synthetic homodetic cyclic peptide comprising N(alpha)-(3-sulfanylpropanoyl)homoarginyl, glycyl, aspartyl, tryptophyl, prolyl and cysteinamide residues connected in sequence and cyclised via a disulfide bond. Derived from a protein found in the venom of the southeastern pygmy rattlesnake, Sistrurus miliarus barbouri, eptifibatide is an anti-coagulant that inhibits platelet aggregation by selectively blocking the platelet glycoprotein IIb/IIIa receptor, so preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands. It is used in the management of unstable angina and in patients undergoing coronary angioplasty and stenting procedures. It has a role as a platelet aggregation inhibitor and an anticoagulant. It is an organic disulfide, a macrocycle and a homodetic cyclic peptide.
Synthetic cyclic hexapeptide that binds to platelet receptor glycoprotein and inhibits platelet aggregation. Derived from venom of the Southeastern pygmy rattlesnake (Sistrurus miliarus barbouri), eptifibatide is a cyclic heptapeptide that belongs to the class of arginin-glycin-aspartat-mimetics.
Eptifibatide is a Platelet Aggregation Inhibitor. The physiologic effect of eptifibatide is by means of Decreased Platelet Aggregation.
Eptifibatide is a cyclical heptapeptide with anticoagulant activity. Eptifibatide selectively and reversibly binds to and blocks the platelet glycoprotein IIb/IIIa receptor. This prevents the binding of fibrinogen, von Willebrand factor, and other adhesive ligands and leads to an inhibition of platelet aggregation and prevents thrombus development.
Cyclic peptide that acts as a platelet glycoprotein IIB-IIIA antagonist, reversibly inhibiting the binding of FIBRINOGEN; VON WILLEBRAND FACTOR; and other adhesive molecules to the GPIIB-IIIA RECEPTORS of platelets. It is used in the management of UNSTABLE ANGINA and in patients undergoing coronary ANGIOPLASTY and stenting procedures.

---

Drug Indication
For treatment of myocardial infarction and acute coronary syndrome.
FDA Label
Eptifibatide Accord is intended for use with acetylsalicylic acid and unfractionated heparin. Eptifibatide Accord is indicated for the prevention of early myocardial infarction in adults presenting with unstable angina or non-Q-wave myocardial infarction, with the last episode of chest pain occurring within 24 hours and with electrocardiogram (ECG) changes and/or elevated cardiac enzymes. Patients most likely to benefit from Eptifibatide Accord treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early PTCA (Percutaneous Transluminal Coronary Angioplasty).
Integrilin is intended for use with acetylsalicylic acid and unfractionated heparin. Integrilin is indicated for the prevention of early myocardial infarction in patients presenting with unstable angina or non-Q-wave myocardial infarction with the last episode of chest pain occurring within 24 hours and with ECG changes and / or elevated cardiac enzymes. Patients most likely to benefit from Integrilin treatment are those at high risk of developing myocardial infarction within the first 3-4 days after onset of acute angina symptoms including for instance those that are likely to undergo an early percutaneous transluminal coronary angioplasty (PTCA).

---

Mechanism of Action
Eptifibatide inhibits platelet aggregation by reversibly binding to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets, thus preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands. Inhibition of platelet aggregation occurs in a dose- and concentration-dependent manner.

---

Therapeutic Uses
Platelet Aggregation Inhibitors
/CLINICAL TRIALS/ ClinicalTrials.gov is a registry and results database of publicly and privately supported clinical studies of human participants conducted around the world. The Web site is maintained by the National Library of Medicine (NLM) and the National Institutes of Health (NIH). Each ClinicalTrials.gov record presents summary information about a study protocol and includes the following: Disease or condition; Intervention (for example, the medical product, behavior, or procedure being studied); Title, description, and design of the study; Requirements for participation (eligibility criteria); Locations where the study is being conducted; Contact information for the study locations; and Links to relevant information on other health Web sites, such as NLM's MedlinePlus for patient health information and PubMed for citations and abstracts for scholarly articles in the field of medicine. Eptifibatide is included in the database.
Integrilin is indicated to decrease the rate of a combined endpoint of death or new myocardial infarction (MI) in patients with ACS (unstable angina (UA)/non-ST-elevation myocardial infarction (NSTEMI)), including patients who are to be managed medically and those undergoing percutaneous coronary intervention (PCI).
Integrilin is indicated to decrease the rate of a combined endpoint of death, new myocardial infarction (MI), or need for urgent intervention in patients undergoing percutaneous coronary intervention (PCI), including those undergoing intracoronary stenting. /Included in US product label/
Eptifibatide has been administered concomitantly with a thrombolytic agent (e.g., alteplase, tenecteplase) in a limited number of patients to prevent coronary artery reocclusion after an acute myocardial infarction. /NOT included in US product label/

---

Drug Warnings
The most frequent and severe adverse effect of eptifibatide therapy is bleeding. Bleeding complications, which usually are minor and develop at vascular access (e.g., femoral puncture) sites (e.g., in patients undergoing percutaneous coronary intervention (PCI)), have been reported in 35-75% of patients receiving various dosages of eptifibatide in clinical studies. Bleeding is an extension of the pharmacologic action of eptifibatide and was classified in clinical trials principally according to criteria of the Thrombolysis in Myocardial Infarction (TIMI) study groups. Minor bleeding generally was defined as spontaneous gross hematuria or spontaneous hematemesis; observed blood loss with a decrease in hemoglobin concentration of 3-5 g/dL or a reduction in hematocrit of at least 10%; or a decrease of 4-5 g/dL or 12-15% in hemoglobin or hematocrit, respectively, with no identifiable bleeding site. Major bleeding was defined as intracranial hemorrhage or overt bleeding associated with a hemoglobin or hematocrit decrease of at least 5 g/dL or at least 15%, respectively.
Because eptifibatide increases the risk of bleeding, the drug is contraindicated in patients with a history of bleeding diathesis or active abnormal bleeding (e.g., elevated hemostatic indices, recent noncompressible vascular punctures GI or genitourinary bleeding) within the previous 30 days. A low hematocrit value (less than 30%) at baseline could represent recent undetected bleeding, and patients with such values may not be able to tolerate additional bleeding episodes; eptifibatide should not be used in these patients. Eptifibatide also is contraindicated in patients with severe uncontrolled hypertension (systolic blood pressure exceeding 200 mm Hg or diastolic blood pressure exceeding 110 mm Hg with antihypertensive therapy); recent (within 6 weeks) major surgery; history of stroke within 30 days or any history of hemorrhagic stroke; current or planned therapy with another GP IIb/IIIa-receptor inhibitor; and patients receiving renal dialysis. No data are available on the use of eptifibatide in patients with serum creatinine concentrations of 4 mg/dL or greater; the dosage should be reduced in patients with serum creatinine concentrations between 2-4 mg/dL.
FDA Pregnancy Risk Category: B /NO EVIDENCE OF RISK IN HUMANS. Adequate, well controlled studies in pregnant women have not shown increased risk of fetal abnormalities despite adverse findings in animals, or, in the absence of adequate human studies, animal studies show no fetal risk. The chance of fetal harm is remote but remains a possibility./
Safety and effectiveness of Integrilin in pediatric patients have not been studied.
For more Drug Warnings (Complete) data for Eptifibatide (15 total), please visit the HSDB record page.

---

Pharmacodynamics
Eptifibatide is an anti-coagulant that selectively and reversibly blocks the platelet glycoprotein IIb/IIIa receptor.

C35H49N11O9S2

831.96

831.315

188627-80-7

Eptifibatide monoacetate;1248559-53-6

448812

White to off-white solid powder

1.6±0.1 g/cm3

1.735

-4.84

10

12

10

57

1520

5

C1C[C@H]2C(=O)N[C@@H](CSSCCC(=O)N[C@H](C(=O)NCC(=O)N[C@H](C(=O)N[C@H](C(=O)N2C1)CC3=CNC4=CC=CC=C43)CC(=O)O)CCCCN=C(N)N)C(=O)N

2-((3R,11S,17S,20S,25aS)-20-((1H-indol-3-yl)methyl)-3-carbamoyl-11-(4-guanidinobutyl)-1,9,12,15,18,21-hexaoxodocosahydro-7H-pyrrolo[2,1-g][1,2]dithia[5,8,11,14,17,20]hexaazacyclotricosin-17-yl)acetic acid

CZKPOZZJODAYPZ-LROMGURASA-N

Eptifibatide Integrilin Integrelin HSDB 8313

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 (e.g. under nitrogen), avoid exposure to moisture and light.

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

DMSO : ~250 mg/mL (~300.50 mM)
H2O : ~50 mg/mL (~60.10 mM)

Solubility in Formulation 1: ≥ 2.08 mg/mL (2.50 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 20.8 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.

---

Solubility in Formulation 2: ≥ 2.08 mg/mL (2.50 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 20.8 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.

---

View More

Solubility in Formulation 3: ≥ 2.08 mg/mL (2.50 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 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

---

Solubility in Formulation 4: 100 mg/mL (120.20 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

---

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