DESCRIPCION

La eptifibatida en un heptapéptido cíclico que contiene 6 aminoácidos y un residuo mercaptopropionilo. Químicamente es el N- 6-(aminoiminometill)-N2 -(3-mercapto-1-oxopropil-L-lisilglicil-L-a-aspartil-L-triptofanil-L-prolil-L-cisteinamida, disulfuro (1-6)-cíclico. La eptifibatida se une al receptor para la glicoproteína IIb/IIIa de las plaquetas humanas inhibiendo su agregación.

Mecanismo de acción

La eptifibatida reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa. When administered intravenously, eptifibatida inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. Platelet aggregation inhibition is reversible following cessation of the eptifibatida infusion; this is thought to result from dissociation of eptifibatida from the platelet. Pharmacodynamics Infusion of eptifibatida into baboons caused a dose-dependent inhibition of ex vivo platelet aggregation, with complete inhibition of aggregation achieved at infusion rates greater than 5 mcg/kg/min. In a baboon model that is refractory to aspirin and heparin, doses of eptifibatida that inhibit aggregation prevented acute thrombosis with only a modest prolongation (2- to 3-fold) of the bleeding time. Platelet aggregation in dogs was also inhibited by infusions of eptifibatida, with complete inhibition at 2 mcg/kg/min. This infusion dose completely inhibited canine coronary thrombosis induced by coronary artery injury (Folts model). Human pharmacodynamic data were obtained in healthy subjects and in patients presenting with unstable angina (UA) or non-Q-wave myocardial infarction (NQMI) and/or undergoing percutaneous coronary interventions. Studies in healthy subjects enrolled only males; patient studies enrolled approximately one third women. In these studies, eptifibatida inhibited ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in a dose- and concentration-dependent manner. The effect of eptifibatida was observed immediately after administration of a 180 mcg/kg intravenous bolus. Table 1 shows the effects on platelet function and bleeding time of the doses of eptifibatida used in the two principal clinical studies. Table 1 Platelet Inhibition and Bleeding Time IMPACT II PURSUIT 135/ 0.5 180/ 2.0 platelet aggregation 15 min. after bolus platelet aggregation at steady state state Inhibition of platelet aggregation 4h after infusion discontinuation <30% <50% infusion discontinuation When administered alone, eptifibatida has no measurable effect on prothrombin time (PT) or activated partial thromboplastin time (aPTT). (See also PRECAUTIONS ). There were no important differences between men and women or between age groups in the pharmacodynamic properties of eptifibatida. Differences among ethnic groups have not been assessed. Pharmacokinetics The pharmacokinetics of eptifibatida are linear and dose-proportional for bolus doses ranging from 90 to 250 mcg/kg and infusion rates from 0.5 to 3 mcg/kg/min. Plasma elimination half-life is approximately 2.5 hours. The recommended regimens of a bolus followed by an infusion produce an early peak level, followed by a small decline with attainment of steady state within 4-6 hours. The extent of eptifibatida binding to human plasma protein is about 25%. Excretion and Metabolism Clearance in patients with coronary artery disease is 55-58 mL/kg/h. In healthy subjects, renal clearance accounts for approximately 50% of total body clearance, with the majority of the drug excreted in the urine as eptifibatida, deamidated eptifibatida, and other, more polar metabolites. No major metabolites have been detected in human plasma. Clinical studies have included 2418 patients with serum creatinine between 1 and 2 mg/dL (for the 180 mcg/kg bolus and the 2 mcg/kg/min infusion) and 7 patients with serum creatinine between 2 and 4 mg/dL (for the 135 mcg/kg bolus and the 0.5 mcg/kg/min infusion), without dose adjustment. No data are available in patients with more severe degrees of renal impairment, but plasma eptifibatida levels are expected to be higher in such patients (see CONTRAINDICATIONS). Special Populations Patients in clinical studies were older than the subjects in clinical pharmacology studies, and they had lower total body eptifibatida clearance and higher eptifibatida plasma levels. Clinical studies were conducted in patients aged 20 to 94 years with coronary artery disease without dose adjustment for age. Because patients over 75 years of age were enrolled into the PURSUIT clinical study only if their body weight exceeded 50 kg, minimal data are available on lighter-weight patients over 75 years of age. Men and women showed no important differences in the pharmacokinetics of eptifibatida. CLINICAL STUDIES eptifibatida was studied in two placebo-controlled, randomized studies, one (PURSUIT) in patients with acute coronary syndrome (unstable angina (UA) or non-Q-wave myocardial infarction (NQMI)), the other (IMPACT II) in patients about to undergo a percutaneous cardiovascular intervention (PCI; balloon angioplasty in most cases, but sometimes directional atherectomy, transluminal extraction catheter atherectomy, rotational ablation atherectomy, or excimer-laser angioplasty). Acute coronary syndrome is defined as prolonged (10 minutes) symptoms of cardiac ischemia within the previous 24 hours associated with either ST-segment changes (elevation between 0.6 mm and 1 mm or depression >0.5 mm), T-wave inversion (>1 mm), or positive CK-MB. This definition includes "unstable angina" and "non-Q-wave myocardial infarction" but excludes myocardial infarction that is associated with Q waves or greater degrees of ST-segment elevation. PURSUIT was a 726-center, 27-country, double-blind, randomized, placebo-controlled study in 10,948 patients presenting with UA or NQMI. Patients could be enrolled only if they had experienced cardiac ischemia at rest (10 minutes) within the previous 24 hours and had either ST-segment changes (elevations between 0.6 mm and 1 mm or depression >0.5 mm), T-wave inversion (>1 mm), or increased CK-MB. Important exclusion criteria included a history of bleeding diathesis, evidence of abnormal bleeding within the previous 30 days, uncontrolled hypertension, major surgery within the previous 6 weeks, stroke within the previous 30 days, any history of hemorrhagic stroke, serum creatinine >2 mg/dL, dependency on renal dialysis, or platelet count <100,000/mm 3 . Patients were randomized to either placebo, eptifibatida 180 mcg/kg bolus followed by a 2 mcg/kg/min infusion (180/2.0), or eptifibatida 180 mcg/kg bolus followed by a 1.3 mcg/kg/min infusion (180/1.3). The infusion was continued for 72 hours, until hospital discharge, or until the time of coronary artery bypass grafting (CABG), whichever occurred first, except that if PCI was performed, the eptifibatida infusion was continued for 24 hours after the procedure, allowing for a duration of infusion up to 96 hours. The lower-infusion-rate arm was stopped after the first interim analysis when the two active-treatment arms appeared to have the same incidence of bleeding. Patient age ranged from 20 to 94 (mean 63) years, and 65% were male. The patients were 89% Caucasian, 6% Hispanic, and 5% Black, recruited in the United States and Canada (40%), Western Europe (39%), Eastern Europe (16%), and Latin America (5%). This was a "real world" study; each patient was managed according to the usual standards of the investigational site; frequencies of angiography, PCI, and CABG therefore differed widely from site to site and from country to country. Of the patients in PURSUIT, 13% were managed with PCI during drug infusion, of whom 50% received intracoronary stents; 87% were managed medically (without PCI during drug infusion). The majority of patients received aspirin (75-325 mg once daily). Heparin was administered intravenously or subcutaneously, at the physician�s discretion, most commonly as an intravenous bolus of 5000 U followed by a continuous infusion of 1000 U/h. For patients weighing less than 70 kg, the recommended heparin bolus dose was 60 U/kg followed by a continuous infusion of 12 U/kg/h. A target aPTT of 50-70 seconds was recommended. A total of 1250 patients underwent PCI within 72 hours after randomization, in which case they received intravenous heparin to maintain an activated clotting time (ACT) of 300-350 seconds. The primary endpoint of the study was the occurrence of death from any cause or new myocardial infarction (MI) (evaluated by a blinded Clinical Endpoints Committee) within 30 days of randomization. Compared to placebo, eptifibatida administered as a 180 mcg/kg bolus followed by a 2 mcg/kg/min infusion significantly (p=0.042) reduced the incidence of endpoint events (see Table 2). The reduction in the incidence of endpoint events in patients receiving eptifibatida was evident early during treatment, and this reduction was maintained through at least 30 days (see Figure 1). Table 2 also shows the incidence of the components of the primary endpoint, death (whether or not preceded by an MI) and new MI in surviving patients at 30 days. Table 2 Clinical Events In The PURSUIT Study Death or MI Placebo (n = 4739) n (%) eptifibatida (180/ 2.0) (n = 4722) n (%) p- value 359 (7.6%) 279 (5.9%) 0.001 552 (11.6%) 477 (10.1%) 0.016 30 days MI (Primary Endpoint) 745 (15.7%) 672 (14.2%) 0.042 177 (3.7%) 165 (3.5%) 568 (12.0%) 507 (10.7%) The effect of eptifibatida in PURSUIT did not appear to vary with patients� age. There were too few non-Caucasian patients to reach any conclusion as to possible differences related to race. Analysis of the PURSUIT results reveals a complex interaction of treatment, gender, and region. Throughout the world, eptifibatida was significantly less beneficial in women than in men, and in the overall study eptifibatida in women was nonsignificantly worse than placebo. These results were, however, strikingly heterogeneous across the several regions; eptifibatida appeared much worse than placebo in women in Latin America, while effects in men and women were scarcely distinguishable (relative risk reductions of 23% and 18%, respectively) in the U.S. and Canada. These results may reflect (a) genuine biological interactions between eptifibatida and gender, (b) interactions between eptifibatida and unknown international differences in concomitant therapy delivered to men and women, and (c) the play of chance, but the relative contributions of these possible factors are unknown. Treatment with eptifibatida reduced clinical events in patients undergoing PCI during drug administration and in those receiving medical management alone. Table 3 shows the incidence of death or MI within 72 hours of randomization. Table 3 Clinical Events (Death or MI) in the PURSUIT Study Within 72 Hours of Randomization Placebo eptifibatida 180/ 2.0 Overall Patient Population At 72 hours 7.6% 5.9% Patients undergoing early PCI procedure (nonfatal MI only) At 72 hours 14.4% 9.0% Patients not undergoing early PCI At 72 hours 6.5% 5.4% All of the effect of eptifibatida was established within 72 hours (during the period of drug infusion), regardless of management strategy. Moreover, for patients undergoing early PCI, a reduction in events was evident prior to the procedure. IMPACT II was a multi-center, double-blind, randomized, placebo-controlled study conducted in the United States in 4010 patients undergoing PCI. Major exclusion criteria included a history of bleeding diathesis, major surgery within 6 weeks of treatment, gastrointestinal bleeding within 30 days, any stroke or structural CNS abnormality, uncontrolled hypertension, PT >1.2 times control, hematocrit <30%, platelet count <100,000/mm 3 , and pregnancy. Patient age ranged from 24 to 89 (mean 60) years, and 75% were male. The patients were 92% Caucasian, 5% Black, and 3% Hispanic. Patients were randomly assigned to one of three treatment regimens, each incorporating a bolus dose initiated immediately prior to PCI followed by a continuous infusion lasting 20-24 hours: 1) 135 mcg/kg bolus followed by a continuous infusion of 0.5 mcg/kg/min of eptifibatida (135/0.5); 2) 135 mcg/kg bolus followed by a continuous infusion of 0.75 mcg/kg/min of eptifibatida (135/0.75); or 3) a matching placebo bolus followed by a matching placebo continuous infusion. Each patient received aspirin and an intravenous heparin bolus of 100 U/kg, with additional bolus infusions of up to 2000 additional units of heparin every 15 minutes to maintain an activated clotting time (ACT) of 300-350 seconds. The primary endpoint was the composite of death, MI, or urgent revascularization, analyzed at 30 days after randomization in all patients who received at least one dose of study drug. As shown in Table 4, each eptifibatida regimen reduced the rate of death, MI, or urgent intervention, although at 30 days, this finding was statistically significant only in the lower-dose eptifibatida group. As in the PURSUIT study, the effects of eptifibatida were seen early and persisted throughout the 30-day period. Table 4 Clinical Events in the IMPACT II Study Placebo n (%) eptifibatida (135/ 0.5) n (%) eptifibatida (135/ 0.75) n (%) Patients Abrupt Closure placebo Death, MI, or Urgent Intervention 24 hours 123 (9.6%) 86 (6.6%) 89 (6.9%) placebo 48 hours 131 (10.2%) 99 (7.6%) 102 (7.9%) placebo 30 days (primary endpoint) 149 (11.6%) 118 (9.1%) 128 (10.0%) placebo Death or MI 30 days 110 (8.6%) 89 (6.8%) 95 (7.4%) placebo 6 months 151 (11.9%)* 136 (10.6%)* 130 (10.3%)* placebo * Kaplan-Meier estimate of event rate At the time of randomization, approximately 25% of the IMPACT II patients suffered from only chronic stable angina, or had had no angina at all since a remote (more than 14 days prior) myocardial infarction. At the other extreme, approximately 40% of the IMPACT II patients had ongoing acute coronary syndromes, including patients with rest angina, others with refractory recurrent angina, others with early post-infarction angina, and others about to receive percutaneous interventions during or immediately following acute myocardial infarction. The remaining patients had various histories of recent and remote acute coronary syndromes; data are not available to describe what fraction of these underwent PCI within only a day or two of an acute episode. The IMPACT II study was not powered to obtain stable estimates of efficacy in subpopulations defined by degree of acuity, but (as shown in Table 5) the data suggest that the benefit of eptifibatida was not limited to patients with ongoing acute coronary syndromes. Table 5 Clinical Events at 30 Days in the IMPACT II Study, Stratified by Acuity at Time of Randomization Classification of Patients (%) Placebo n (%) eptifibatida 135/ 0.5 n (%) eptifibatida 135/ 0.75 n (%) Ongoing ACS, MI ongoing or within past 24h (41.3%) 538 (11.5%) 532 (10.0%) 527 (10.6%) Others (58.7%) 747 (11.6%) 768 (8.5%) 759 (9.5%) Special Offers Lose 10 Lbs in 5 Weeks. Free Diet Profile! FREE Asthma Guide From our sponsors Hepatitis C Treatment #1 Soy Protein Help use the natural insulin in you Advertisement