Mechanism of action

Metalyse® functions similar to naturally occurring human t-PA, which is the natural endogenous lytic pathway in the circulation, dissolving blood clots. It is a protease that binds to fibrin in thrombi and selectively catalyses the conversion of thrombus bound plasminogen to the active enzyme plasmin. As plasmin is a protease, it breaks down the fibrin matrix of a thrombus, thus resolving the clot itself. Plasmin is non-specific and can attack other proteins including fibrinogen, the precursor of fibrin. This may increase the risk of bleeding as it can dissolve other clots in the body, and prevent new clotting taking place.

Metalyse® is more specific than streptokinase, targeting plasminogen bound to a fibrin clot as opposed to circulating fibrinogen. Therefore it attains higher early patency rates. In rabbits with thrombotically occluded arteries, Metalyse® produced faster and more complete recanalisation compared with alteplase, without increasing systemic plasmin generation or peripheral bleeding.

Heparin inhibits clotting by affecting fibrin formation and modifying platelet aggregation. Metalyse® administered in conjunction with heparin has achieved a better clinical effect, notably improved angiographic patency. Given early enough, Metalyse® will remove the thrombus, re-establish blood flow, limit myocardial damage and improve prognosis by preserving left ventricular function.


The clinical pharmacology of Metalyse® in humans with acute myocardial infarction was assessed in two Thrombolysis in Myocardial Infarction (TIMI) trials and in the Assessment of the Safety and Efficacy of a New Thrombolytic: TNK-tPA (ASSENT-1) study:

  • TIMI 10A: This was a phase I, dose ranging trial designed to evaluate the pharmacokinetics, safety and efficacy of Metalyse® in patients with acute myocardial infarction. TIMI 10A showed that bolus administration of Metalyse® was associated with acceptable safety and efficacy profiles;
  • TIMI 10B: This trial was designed to compare prospectively the angiographic efficacy and safety of Metalyse® and alteplase.
  • ASSENT-1: This phase II clinical study assessed the safety of Metalyse® at doses of 30, 40 and 50 mg in a large cohort of patients in order to identify an appropriate dose for testing in a large mortality trial.

Metalyse® plasma concentration-time profiles were obtained from a total of 179 patients with acute myocardial infarction in the TIMI 10A and TIMI 10B studies. Metalyse® exhibited biphasic disposition; the initial disposition phase was predominant with a mean half-life of 17-24 minutes, and the mean terminal half-life was 65-132 min.

Over the clinically relevant dose range of 30-50 mg investigated in TIMI 10B, mean clearance (CL) was 105 ml/min. The mean initial volume of distribution (V1) was 4.2-6.3 L, approximating plasma volume, and volume of distribution at steady state was 6.1-9.9 L, suggesting limited extravascular distribution or binding. Hepatic elimination is the major clearance mechanism for Metalyse®.

Bodyweight and age were found to significantly influence significantly both clearance and V1. Total bodyweight explained 19% of the variability in clearance and 11% of the variability in V1, and a 10 kg increase in total bodyweight resulted in a 9.6 mL/min increase in clearance. This relationship aided the development of a rationale for the weight adjusted dose regimen for tenecteplase. Age explained only a further 11% of the variability in clearance.

Blood concentrations of Metalyse® vs alteplase over time in the TIMI 10B trial

Blood  concentration  of  Metalyse®  vs  alteplase  over  time  in  the  TIMI  10B  trial           Plasma concentration of Tenecteplase and alteplase at different time intervals

The figure illustrates the time-dependence of plasma concentrations of alteplase (rt-PA) and Metalyse® (TNK-tPA) at 30, 40 and 50 mg in a subset of patients from the TIMI 10B study. Systemic exposure to tenecteplase at all of these doses, as measured by the peak plasma concentration and area under the curve, was higher than for a 90 minute infusion of 100 mg alteplase, thus ensuring rapid restoration of coronary patency. Due to the improved fibrin specificity of Metalyse®, this increased systemic exposure did not compromise clinical safety and resulted in less serious bleeding events compared to alteplase.

The TIMI trials showed by direct comparison that Metalyse® had far less effect on systemic coagulation factors than front-loaded alteplase, thus supporting pre-clinical evidence that Metalyse® is more fibrin specific.

In TIMI 10A Metalyse® showed a dose dependent fall in fibrinogen levels. In TIMI 10B, there was a less than 15% reduction in fibrinogen over the first 6 hours in patients treated with the maximum dose of Metalyse® (10,000 U, corresponding to 50 mg), whereas alteplase caused an approximately 50% decrease in fibrinogen levels.

In TIMI 10B there was a less than 25% reduction in plasminogen levels in patients treated with the maximum dose of Metalyse® (10,000 U, corresponding to 50 mg), whereas alteplase caused an approximately 50% decrease in plasminogen levels.

Furthermore, Metalyse® was associated with a 4-5 times greater consumption of alpha2-antiplasmin, which resulted in an increase in the plasma level of plasmin-alpha2-antiplasmin complexes by the same magnitude.

  1. Benedict et al. New variant of human tissue plasminogen activator (TPA) with enhanced efficacy and lower incidence of bleeding compared with recombinant human TPA. Circulation 1995; 92 (10): 3032-3040.
  2. Cannon et al. TNK-tissue plasminogen activator in acute myocardial infarction. Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A dose-ranging trial. Circulation 1997; 95 (2): 351-356.
  3. Cannon et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. Circulation 1998;98:2805-2814.
  4. GUSTO III Investigators. A comparison of reteplase with alteplase for acute myocardial infarction. N Engl J Med 1997; 337 (16): 1118-1123.