Tirofiban pharmacokinetics and molecular data

Clinical Pharmacology

Mechanism of Action

Aggrastat is a reversible antagonist of fibrinogen binding to the GP lIb/lIla receptor, the major platelet surface receptor involved in platelet aggregation. When administered intravenously, Aggrastat inhibits ex vivo platelet aggregation in a dose- and concentration-dependent manner.

When given according to the recommended regimen, >90% inhibition is attained by the end of the 30-minute infusion. Platelet aggregation inhibition is reversible following cessation of the infusion of Aggrastat.

Pharmacokinetics

Tirofiban has a half-life of approximately 2 hours. It is cleared from the plasma largely by renal excretion, with about 65% of an administered dose appearing in urine and about 25% in feces, both largely as unchanged tirofiban. Metabolism appears to be limited.

Tirofiban is not highly bound to plasma proteins and protein binding is concentration independent over the range of 0.01 to 25 mcg/mL. Unbound fraction in human plasma is 35%. The steady state volume of distribution of tirofiban ranges from 22 to 42 liters.

In healthy subjects, the plasma clearance of tirofiban ranges from 213 to 314 mL/min. Renal clearance accounts for 39 to 69% of plasma clearance. The recommended regimen of a loading infusion followed by a maintenance infusion produces a peak tirofiban plasma concentration that is similar to the steady state concentration during the infusion. In patients with coronary artery disease, the plasma clearance of tirofiban ranges from 152 to 267 mL/min; renal clearance accounts for 39% of plasma clearance.

Special Populations

Gender

Plasma clearance of tirofiban in patients with coronary artery disease is similar in males and females. Elderly

Plasma clearance of tirofiban is about 19 to 26% lower in elderly (>65 years) patients with coronary artery disease than in younger (≤65 years) patients.

Race

No difference in plasma clearance was detected in patients of different races.

Hepatic Insufficiency

In patients with mild to moderate hepatic insufficiency, plasma clearance of tirofiban is not significantly different from clearance in healthy subjects.

Renal Insufficiency

Plasma clearance of tirofiban is significantly decreased (>50%) in patients with creatinine clearance <30 mL/min, including patients requiring hemodialysis (see DOSAGE AND ADMINISTRATION, Recommended Dosage).Tirofiban is removed by hemodialysis.

Pharmacodynamics

Aggrastat inhibits platelet function, as demonstrated by its ability to inhibit ex vivo adenosine phosphate (ADP)-induced platelet aggregation and prolong bleeding time in healthy subjects and patients with coronary artery disease. The time course of inhibition parallels the plasma concentration profile of the drug. Following discontinuation of an infusion of Aggrastat, 0.10 mcg/kg/min, ex vivo platelet aggregation returns to near baseline in approximately 90% of patients with coronary artery disease in 4 to 8 hours. The addition of heparin to this regimen does not significantly alter the percentage of subjects with >70% inhibition of platelet aggregation (IPA), but does increase the average bleeding time, as well as the number of patients with bleeding times prolonged to >30 minutes.

In patients with unstable angina, a two-staged intravenous infusion regimen of Aggrastat (loading infusion of 0.4 mcg/kg/min for 30 minutes followed by 0.1 mcg/kg/min for up to 48 hours in the presence of heparin and aspirin), produces approximately 90% inhibition of ex vivo ADP-induced platelet aggregation with a 2.9-fold prolongation of bleeding time during the loading infusion. Inhibition persists over the duration of the maintenance infusion.

Clinical Trials

Three large-scale clinical studies were conducted to study the efficacy and safety of Aggrastat in the management of patients with Acute Coronary Syndrome (unstable angina/non-Q-wave myocardial infarction). Acute Coronary Syndrome is characterized by prolonged (≥10 minutes) or repetitive symptoms of cardiac ischemia occurring at rest or with minimal exertion, associated with either ischemic ST-T wave changes on electrocardiogram (ECG) or elevated cardiac enzymes. The definition includes “unstable angina” and “non-Q-wave myocardial infarction” but excludes myocardial infarction that is associated with Q-waves or non-transient ST-segment elevation. The three studies examined Aggrastat alone and as an addition to heparin, prior to and after angioplasty (if indicated) (PRISM-PLUS), in comparison to heparin in a similar population (PRISM), and in addition to heparin in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) or atherectomy (RESTORE). These trials are discussed in detail below.

PRISM-PLUS (Platelet Receptor Inhibition for lschemic Syndrome Management—Patients Limited by Unstable Signs and Symptoms)

In the multi-center, randomized, parallel, double-blind PRISM-PLUS trial, the use of Aggrastat in combination with heparin (n=773) was compared to heparin alone (n=797) in patients with documented unstable angina/non-Q-wave myocardial infarction within 12 hours of entry into the study and initiation of treatment. All patients with unstable angina/non-Q-wave myocardial infarction had cardiac ischemia documented by ECG or had elevated cardiac enzymes. Patients who were medically managed or who subsequently underwent revascularization procedures were studied. The mean age of the population was 63 years; 32% of patients were female and approximately half of the population presented with non- Q-wave myocardial infarction. Exclusions included contraindications to anticoagulation (see CONTRAINDICATIONS), decompensated heart failure, platelet count <150,000/mm3, and creatinine >2.5 mg/dL. In this study, patients were randomized to either Aggrastat (30 minute loading infusion of 0.4 mcg/kg/min followed by a maintenance infusion of 0.10 mcg/kg/min) and heparin (bolus of 5,000 units (U) followed by an infusion of 1,000 U/hr titrated to maintain an activated partial thromboplastin time (APTT) of approximately 2 times control), or heparin alone (bolus of 5,000 U followed by an infusion of 1,000 U/hr titrated to maintain an APTT of approximately 2 times control). All patients received concomitant aspirin unless contraindicated. Patients underwent 48 hours of medical stabilization on study drug therapy, and they were to undergo angiography before 96 hours (and, if indicated, angioplasty/atherectomy, while continuing on Aggrastat and heparin for 12-24 hours after the procedure). Some patients went on to coronary artery bypass grafting (CABG) after cessation of drug therapy. Aggrastat and heparin could be continued for up to 108 hours. On average, patients received Aggrastat for 71.3 hours. A third group of patients was initially randomized to Aggrastat alone (no heparin). This arm was stopped when the group was found, at an interim look, to have greater mortality than the other two groups. Note, however, that a direct comparison of heparin and tirofiban alone in the PRISM study (see below) did not show excess mortality.

The primary endpoint of the study was a composite of refractory ischemia, new myocardial infarction and death at 7 days after initiation of Aggrastat and heparin. At the primary endpoint, there was a 32% risk reduction in the overall composite. The components of the composite were examined separately (they total more than the composite because a patient could have more than one, e.g., by dying after having a new infarction). There was a 47% risk reduction in myocardial infarction and a 30% risk reduction in refractory ischemia.

The benefit seen at 7 days was maintained over time. At 30 days, the risk of the composite endpoint was reduced by 22% (p=0.029) and there was a 30% reduction in the composite of myocardial infarction and death (p=0.027). At 6 months, the risk of the composite endpoint was reduced by 19% (p=0.024).

PRISM-PLUS was not designed to provide definitive results in subsets of the overall population. Nonetheless, results were examined for demographic (age, gender, race) subsets and for people who did and did not receive PTCA, atherectomy, or CABG.

In PRISM-PLUS, there was a consistent treatment effect in patients either greater or less than 65 years old, and in men and women. Too few non-Caucasians were enrolled to make a definite statement about racial differences in treatment effect.

Approximately 90% of patients in the PRISM-PLUS study underwent coronary angiography and 30% underwent angioplasty/atherectomy during the first 30 days of the study. The majority of these patients continued on study drug throughout these procedures. Aggrastat was continued for 12-24 hours (average 15 hours) after angioplasty/atherectomy. The effects of Aggrastat at Day 30 did not appear to differ among the sub-populations that did or did not receive PTCA or CABG, both prior to and after the procedure.

A sub-study in PRISM-PLUS of angiograms after 48 to 96 hours found that there was a significant decrease in the extent of angiographically apparent thrombus in patients treated with Aggrastat in combination with heparin compared to heparin alone. In addition, flow in the affected coronary artery was significantly improved.