(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.
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.
◉ 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.
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.
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.
The present invention provides processes for preparation of eptifibatide that involve coupling of amino acids in a (2+5), (4+3) and (3+4) sequence method. The invention further provides products produced by the described processes, novel compounds that can be used as synthetic intermediates for the preparation of eptifibatide.
An assay for screening snake venom for the presence or absence of platelet aggregation inhibitors (PAIs) based on specific receptor binding is described. Using this assay, the identification and characterization of PAIs in a wide range of snake venom samples was accomplished. The isolated and purified PAI from several of these active snake venoms is described and characterized. In addition, PAIs lacking the Arg-Gly-Asp (RGD) adhesion sequence but containing K*-(G/Sar)-D wherein K* is a modified lysyl residue of the formula R.sup.1.sub.2 N(CH.sub.2).sub.4 CHNHCO-- wherein each R.sup.1 is independently H, alkyl(1-6C) or at most one R.sup.1 is R.sup.2 --C.dbd.NR.sup.3 wherein R.sup.2 is H, alkyl(1-6C), phenyl or benzyl, or is NR.sup.4.sub.2 in which each R.sup.4 is independently H or alkyl(1-6C) and R.sup.3 is H, alkyl(1-6C), phenyl or benzyl, or R.sup.2 --C.dbd.NR.sup.3 is a radical selected from the group consisting of: ##STR1## where m is an integer of 2-3, and each R.sup.5 is independently H or alkyl(1-6C); and wherein one or two (CH.sub.2) may be replaced by O or S provided said O or S is not adjacent to another heteroatom are prepared and shown to specifically inhibit the binding of fibrinogen or von Willebrand Factor to GP IIb-IIIa.
The present invention provides processes for preparation of eptifibatide that involve coupling of amino acids in a (2+5), (4+3) and (3+4) sequence method. The invention further provides products produced by the described processes, novel compounds that can be used as synthetic intermediates for the preparation of eptifibatide.
[EN] PROCESSES FOR PREPARING EPTIFIBATIDE<br/>[FR] PROCÉDÉS POUR PRÉPARER L'EPTIFIBATIDE
申请人：LAURUS LABS PRIVATE LTD
公开号：WO2013014527A1
公开（公告）日：2013-01-31
The present invention provides processes for preparation of eptifibatide that involve coupling of amino acids in a (2+5), (4+3) and (3 +4) sequence method. The invention further provides products produced by the described processes, novel compounds that can be used as synthetic intermediates for the preparation of eptifibatide.
