Integrilin (Eptifibatide) - Description and Clinical Pharmacology

For Intravenous Administration

DESCRIPTION

Eptifibatide is a cyclic heptapeptide containing six amino acids and one mercaptopropionyl (des-amino cysteinyl) residue. An interchain disulfide bridge is formed between the cysteine amide and the mercaptopropionyl moieties. Chemically it is N⁶-(aminoiminomethyl)-N²-(3-mercapto-1-oxopropyl-L-lysylglycyl-L-α-aspartyl-L-tryptophyl-L-prolyl-L-cysteinamide, cyclic (1→6)-disulfide. Eptifibatide binds to the platelet receptor glycoprotein (GP) IIb/IIIa of human platelets and inhibits platelet aggregation.

The eptifibatide peptide is produced by solution-phase peptide synthesis, and is purified by preparative reverse-phase liquid chromatography and lyophilized. The structural formula is:

INTEGRILIN^® (eptifibatide) Injection is a clear, colorless, sterile, non-pyrogenic solution for intravenous (IV) use with an empirical formula of C₃₅H₄₉N₁₁O₉S₂ and a molecular weight of 831.96. Each 10-mL vial contains 2 mg/mL of eptifibatide and each 100-mL vial contains either 0.75 mg/mL of eptifibatide or 2 mg/mL of eptifibatide. Each vial of either size also contains 5.25 mg/mL citric acid and sodium hydroxide to adjust the pH to 5.35.

CLINICAL PHARMACOLOGY

Mechanism of Action

Eptifibatide reversibly inhibits platelet aggregation by preventing the binding of fibrinogen, von Willebrand factor, and other adhesive ligands to GP IIb/IIIa. When administered intravenously, eptifibatide inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner. Platelet aggregation inhibition is reversible following cessation of the eptifibatide infusion; this is thought to result from dissociation of eptifibatide from the platelet.

Pharmacodynamics

Infusion of eptifibatide into baboons caused a dose-dependent inhibition of ex vivo platelet aggregation, with complete inhibition of aggregation achieved at infusion rates greater than 5.0 µg/kg/min. In a baboon model that is refractory to aspirin and heparin, doses of eptifibatide 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 eptifibatide, with complete inhibition at 2.0 µg/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-ST-segment elevation myocardial infarction (NSTEMI) and/or undergoing percutaneous coronary interventions. Studies in healthy subjects enrolled only males; patient studies enrolled approximately one-third women. In these studies, eptifibatide inhibited ex vivo platelet aggregation induced by adenosine diphosphate (ADP) and other agonists in a dose- and concentration-dependent manner. The effect of eptifibatide was observed immediately after administration of a 180-µg/kg intravenous bolus. Table 1 shows the effects of dosing regimens of eptifibatide used in the IMPACT II and PURSUIT studies on ex vivo platelet aggregation induced by 20 µM ADP in PPACK-anticoagulated platelet-rich plasma and on bleeding time. The effects of the dosing regimen used in ESPRIT on platelet aggregation have not been studied.

Table 1 Platelet Inhibition and Bleeding Time

	IMPACT II 135/0.5135-µg/kg bolus followed by a continuous infusion of 0.5 µg/kg/min.	PURSUIT 180/2.0180-µg/kg bolus followed by a continuous infusion of 2.0 µg/kg/min.
Inhibition of platelet aggregation 15 min after bolus	69%	84%
Inhibition of platelet aggregation at steady state	40–50%	>90%
Bleeding-time prolongation at steady state	<5×	<5×
Inhibition of platelet aggregation 4h after infusion discontinuation	<30%	<50%
Bleeding-time prolongation 6h after infusion discontinuation	1×	1.4×

The eptifibatide dosing regimen used in the ESPRIT study included two 180-µg/kg bolus doses given 10 minutes apart combined with a continuous 2.0 µg/kg/min infusion.

When administered alone, eptifibatide has no measurable effect on prothrombin time (PT) or activated partial thromboplastin time (aPTT) (see also PRECAUTIONS, Drug Interactions section).

There were no important differences between men and women or between age groups in the pharmacodynamic properties of eptifibatide. Differences among ethnic groups have not been assessed.

Pharmacokinetics

The pharmacokinetics of eptifibatide are linear and dose-proportional for bolus doses ranging from 90 to 250 µg/kg and infusion rates from 0.5 to 3.0 µg/kg/min. Plasma elimination half-life is approximately 2.5 hours. Administration of a single 180-µg/kg bolus combined with an infusion produces an early peak level, followed by a small decline prior to attaining steady state (within 4–6 hours). This decline can be prevented by administering a second 180-µg/kg bolus 10 minutes after the first. The extent of eptifibatide binding to human plasma protein is about 25%. Clearance in patients with coronary artery disease is about 55 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 eptifibatide, deaminated eptifibatide, and other, more polar metabolites. No major metabolites have been detected in human plasma.

In patients with moderate to severe renal insufficiency (creatinine clearance <50 mL/min using the Cockcroft-Gault equation), the clearance of eptifibatide is reduced by approximately 50% and steady-state plasma levels approximately doubled (see WARNINGS and DOSAGE AND ADMINISTRATION).

Special Populations

Patients in clinical studies were older (range 20–94 years) than those in the clinical pharmacology studies. Elderly patients with coronary artery disease demonstrated higher plasma levels and lower total body clearance of eptifibatide when given the same dose as younger patients. Limited data are available on lighter weight (<50 kg) patients over 75 years of age.

No studies have been conducted in patients with hepatic impairment.

Males and females have not demonstrated any clinically significant differences in the pharmacokinetics of eptifibatide.

CLINICAL STUDIES

Eptifibatide was studied in three placebo-controlled, randomized studies. PURSUIT evaluated patients with acute coronary syndromes: unstable angina (UA) or non-ST-segment elevation MI (NSTEMI). Two other studies, ESPRIT and IMPACT II, evaluated patients about to undergo a percutaneous coronary intervention (PCI). Patients underwent primarily balloon angioplasty in IMPACT II and intracoronary stent placement, with or without angioplasty, in ESPRIT.

Non-ST-segment Elevation Acute Coronary Syndrome

Non-ST-segment elevation 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 "NSTEMI" but excludes myocardial infarction that is associated with Q waves or greater degrees of ST-segment elevation.

PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using INTEGRILIN^® Therapy)

PURSUIT was a 726-center, 27-country, double-blind, randomized, placebo-controlled study in 10,948 patients presenting with UA or NSTEMI. 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 >2.0 mg/dL, dependency on renal dialysis, or platelet count <100,000/mm³.

Patients were randomized to either placebo, eptifibatide 180-µg/kg bolus followed by a-2.0 µg/kg/min infusion (180/2.0), or eptifibatide 180-µg/kg bolus followed by a 1.3-µg/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 eptifibatide 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 to 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 to 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, eptifibatide administered as a 180-µg/kg bolus followed by a 2.0-µg/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 eptifibatide 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	Eptifibatide (180/2.0) (n = 4722) (%)	P -value
3 days	359     (7.6%)	279     (5.9%)	0.001
7 days	552   (11.6%)	477   (10.1%)	0.016
30 days
Death or MI (Primary Endpoint)	745   (15.7%)	672   (14.2%)	0.042
Death	177     (3.7%)	165     (3.5%)
Nonfatal MI	568   (12.0%)	507   (10.7%)

Figure 1: Kaplan-Meier Plot of Time to Death or Myocardial Infarction Within 30 Days of Randomization

Treatment with eptifibatide prior to determination of patient management strategy reduced clinical events regardless of whether patients ultimately underwent diagnostic catheterization, revascularization (ie, PCI or CABG surgery) or continued to receive medical management alone. Table 3 shows the incidence of death or MI within 72 hours.

Table 3 Clinical Events (Death or MI) in the PURSUIT Study Within 72 Hours of Randomization

	Placebo	Eptifibatide 180/2.0
Overall Patient Population	n=4739	n=4722
– At 72 hours	7.6%	5.9%
Patients undergoing early PCI	n=631	n=619
– Pre-procedure (nonfatal MI only)	5.5%	1.8%
– At 72 hours	14.4%	9.0%
Patients not undergoing early PCI	n=4108	n=4103
– At 72 hours	6.5%	5.4%

All of the effect of eptifibatide 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.

An analysis of the results by sex suggests that women who would not routinely be expected to undergo percutaneous coronary intervention (PCI) receive less benefit from eptifibatide (95% confidence limits for relative risk of 0.94 to 1.28) than do men (0.72 to 0.90). This difference may be a true treatment difference, the effect of other differences in these subgroups, or a statistical anomaly. No differential outcomes were seen between male and female patients undergoing PCI (see results for ESPRIT).

Follow-up data were available through 165 days for 10,611 patients enrolled in the PURSUIT trial (96.9 percent of the initial enrollment). This follow-up included 4566 patients who received eptifibatide at the 180/2.0 dose. As reported by the investigators, the occurrence of death from any cause or new myocardial infarction for patients followed for at least 165 days was reduced from 13.6 percent with placebo to 12.1 percent with eptifibatide 180/2.0.

Percutaneous Coronary Intervention

IMPACT II (INTEGRILIN^® to Minimize Platelet Aggregation and Prevent Coronary Thrombosis II)

IMPACT II was a multicenter, 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/mm³, 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. Forty-one percent of the patients underwent PCI for ongoing ACS. 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 to 24 hours: 1) 135-µg/kg bolus followed by a continuous infusion of 0.5 µg/kg/min of eptifibatide (135/0.5); 2) 135-µg/kg bolus followed by a continuous infusion of 0.75-µg/kg/min of eptifibatide (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 to 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 eptifibatide regimen reduced the rate of death, MI, or urgent intervention, although at 30 days, this finding was statistically significant only in the lower-dose eptifibatide group. As in the PURSUIT study, the effects of eptifibatide were seen early and persisted throughout the 30-day period.

Table 4 Clinical Events in the IMPACT II Study

	Placebo	Eptifibatide (135/0.5)	Eptifibatide (135/0.75)
	n (%)	n (%)	n (%)
Patients	1285	1300	1286
Abrupt Closure	65 (5.1%)	36 (2.8%)	43 (3.3%)
P -value vs placebo		0.003	0.030
Death, MI, or Urgent Intervention
24 hours	123 (9.6%)	86 (6.6%)	89 (6.9%)
P -value vs placebo		0.006	0.014
48 hours	131 (10.2%)	99 (7.6%)	102 (7.9%)
P -value vs placebo		0.021	0.045
30 days (primary endpoint)	149 (11.6%)	118 (9.1%)	128 (10.0%)
P -value vs placebo		0.035	0.179
Death or MI
30 days	110 (8.6%)	89 (6.8%)	95 (7.4%)
P -value vs placebo		0.102	0.272
6 months	151 (11.9%) 1	136 (10.6%)	130 (10.3%)
P -value vs placebo		0.297	0.182