Chemical formula: C₂₂H₃₆N₂O₅S Molecular mass: 440.597 g/mol PubChem compound: 60947
Tirofiban is a non-peptidal antagonist of the GP IIb/IIIa receptor, an important platelet surface receptor involved in platelet aggregation. Tirofiban prevents fibrinogen from binding to the GP IIb/IIIa receptor, thus blocking platelet aggregation.
Tirofiban leads to inhibition of platelet function, evidenced by its ability to inhibit ex vivo ADP-induced platelet aggregation and to prolong bleeding time (BT). Platelet function returns to baseline within eight hours after discontinuation. The extent of this inhibition runs parallel to the tirofiban plasma concentration.
In the 0.4 microgram/kg/min infusion regimen of tirofiban, in the presence of unfractionated heparin and ASA, tirofiban produced a more than 70% (median 89%) inhibition of ex vivo ADP-induced platelet aggregation in 93% of the patients, and a prolongation of the bleeding time by a factor of 2.9 during infusion. Inhibition was achieved rapidly with the 30-minute loading infusion and was maintained over the duration of the infusion.
The tirofiban 25 microgram/kg dose bolus regimen (followed by 18-24 hour maintenance infusion of 0.15 microgram/kg/min), in the presence of unfractionated heparin and oral antiplatelet therapy, produced an average ADP-induced inhibition of maximal aggregation 15 to 60 minutes after onset of treatment of 92% to 95% as measured with light transmission aggregometry (LTA).
Tirofiban is not strongly bound to plasma protein, and protein binding is concentration-independent in the range of 0.01–25 microgram/ml. The unbound fraction in human plasma is 35%.
The distribution volume of tirofiban in the steady state is about 30 litres.
Experiments with 14C-labelled tirofiban showed the radioactivity in urine and faeces to be emitted chiefly by unchanged tirofiban. The radioactivity in circulating plasma originates mainly from unchanged tirofiban (up to 10 hours after administration).
These data suggested limited metabolisation of tirofiban.
After intravenous administration of 14C-labelled tirofiban to healthy subjects, 66% of the radioactivity was recovered in the urine, 23% in the faeces. The total recovery of radioactivity was 91%. Renal and biliary excretion contribute significantly to the elimination of tirofiban.
In healthy subjects the plasma clearance of tirofiban is about 250 ml/min. Renal clearance is 39–69% of plasma clearance. The half-life is about 1.5 hours.
The plasma clearance of tirofiban in patients with coronary heart disease is similar in men and women.
The plasma clearance of tirofiban is about 25% less in elderly (>65 years) patients with coronary heart disease in comparison to younger (65 years) patients.
No difference was found in the plasma clearance between patients of different ethnic groups.
In patients with unstable angina pectoris or NQWMI the plasma clearance was about 200 ml/min, the renal clearance 39% of the plasma clearance. The half-life is about two hours.
In clinical studies, patients with decreased renal function showed a reduced plasma clearance of tirofiban depending on the degree of impairment of creatinine clearance. In patients with a creatinine clearance of less than 30 ml/min, including haemodialysis patients, the plasma clearance of tirofiban is reduced to a clinically relevant extent (over 50%). Tirofiban is removed by haemodialysis.
There is no evidence of a clinically significant reduction of the plasma clearance of tirofiban in patients with mild to moderate liver failure. No data are available on patients with severe liver failure.
The plasma clearance of tirofiban in patients receiving one of the following drugs was compared to that in patients not receiving that drug in a sub-set of patients (n=762) in the PRISM study. There were no substantial (>15%) effects of these drugs on the plasma clearance of tirofiban: acebutolol, alprazolam, amlodipine, aspirin preparations, atenolol, bromazepam, captopril, diazepam, digoxin, diltiazem, docusate sodium, enalapril, furosemide, glibenclamide, unfractionated heparin, insulin, isosorbide, lorazepam, lovastatin, metoclopramide, metoprolol, morphine, nifedipine, nitrate preparations, oxazepam, paracetamol, potassium chloride, propranolol, ranitidine, simvastatin, sucralfate and temazepam.
The pharmacokinetics and pharmacodynamics of Tirofiban were investigated when concomitantly administered with enoxaparin (1 milligram/kg subcutaneously every 12 hours) and compared with the combination of Tirofiban and unfractionated heparin. There was no difference in the clearance of Tirofiban between the two groups.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity and genotoxicity.
Fertility and reproductive performance were not affected in studies with male and female rats given intravenous doses of tirofiban hydrochloride up to 5 mg/kg/day. These dosages are approximately 22-fold higher than the maximum recommended daily dose in humans.
However, animal studies are insufficient to draw conclusions with respect to reproductive toxicity in humans.
Tirofiban crosses the placenta in rats and rabbits.
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