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

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