A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Integrilin Pharmacology, Pharmacokinetics, Studies, Metabolism - Eptifibatide
Integrilin Pharmacology, Pharmacokinetics, Studies, Metabolism - Eptifibatide
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 mcg/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 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, 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 mcg/kg intravenous
bolus. Table 1 shows the effects on platelet
function and bleeding
time of the doses of eptifibatide
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, eptifibatide 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 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 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 eptifibatide 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 eptifibatide, deamidated eptifibatide, 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
eptifibatide 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
eptifibatide clearance and higher eptifibatide 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 eptifibatide.
CLINICAL STUDIES
Eptifibatide 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,
eptifibatide 180 mcg/kg bolus
followed by a 2 mcg/kg/min infusion
(180/2.0), or eptifibatide 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 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 50-70 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,
eptifibatide 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 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)
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 eptifibatide
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, eptifibatide was significantly
less beneficial in women than in men, and in the overall study eptifibatide
in women was nonsignificantly worse than placebo. These results
were, however, strikingly heterogeneous across the several regions;
eptifibatide 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 eptifibatide
and gender, (b) interactions
between eptifibatide 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 eptifibatide 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
|
Eptifibatide
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
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.
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 eptifibatide (135/0.5); 2) 135 mcg/kg
bolus followed by a continuous infusion
of 0.75 mcg/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 300-350 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
n (%)
|
Eptifibatide
(135/ 0.5)
n (%)
|
Eptifibatide
(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 eptifibatide 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 (%)
|
Eptifibatide
135/ 0.5
n (%)
|
Eptifibatide
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%) |
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