Metalyse 25 mg Mechanism of Action

Pharmacotherapeutic group: Antithrombotic agents. ATC code: B01AD11.
Pharmacology: Pharmacodynamics: Mode of action: Tenecteplase is a recombinant fibrin-specific plasminogen activator that is derived from native t-PA by modifications at three sites of the protein structure. It binds to the fibrin component of the thrombus (blood clot) and selectively converts thrombus-bound plasminogen to plasmin, which degrades the fibrin matrix of the thrombus. Tenecteplase has higher fibrin specificity and greater resistance to inactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.
Pharmacodynamics: After administration of tenecteplase dose dependent consumption of α2-antiplasmin (the fluid-phase inhibitor of plasmin) with consequent increase in the level of systemic plasmin generation have been observed. This observation is consistent with the intended effect of plasminogen activation. In comparative studies a less than 15% reduction in fibrinogen and a less than 25% reduction in plasminogen were observed in subjects treated with the maximum dose of tenecteplase (10,000 U, corresponding to 50 mg), whereas alteplase caused an approximately 50% decrease in fibrinogen and plasminogen levels. No clinically relevant antibody formation was detected at 30 days.
Clinical trials: AcT study: The Alteplase Compared to Tenecteplase (AcT) trial, was designed as a pragmatic, registry based, prospective, randomized, open label, controlled trial of intravenous tenecteplase vs. intravenous alteplase to provide evidence that tenecteplase is non-inferior to alteplase in patients with acute ischemic stroke within 4.5 h from last known well otherwise eligible for intravenous thrombolysis as per current guidelines. The trial achieved its primary outcome demonstrating a clinically relevant non inferiority with tenecteplase 0.25 mg/kg (max. 25 mg) vs alteplase 0.9 mg/kg (max. 90 mg): 296 (36.9%) of 802 patients in the tenecteplase group and 266 (34.8%) of 765 in the alteplase group had an mRS score of 0-1 at 90-120 days (unadjusted risk difference 2.1% [95% CI - 2.6 to 6.9], meeting the prespecified non-inferiority threshold of -5%).
Key safety outcomes were symptomatic intracerebral haemorrhage, orolingual angio-oedema, and extracranial bleeding requiring blood transfusion, all occurring within 24 h of thrombolytic administration, and 90-day all-cause mortality.
There were no meaningful differences in the rate of 24 h symptomatic intracerebral haemorrhage. Rates of imaging-defined intracranial haemorrhage (assessed blinded to symptom status and treatment allocation) showed no differences between the two groups, and the imaging-defined rates of type 2 parenchymal haematoma (i.e., haematoma occupying ≥30% of infarct with obvious mass effect) were similar to the observed rates of symptomatic intracerebral haemorrhage in the trial. There were no meaningful differences in the rate of 90-day mortality 90 days from treatment. Orolingual angioedema and peripheral bleeding requiring blood transfusion were rare and similar in both groups (see Table 1).

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EXTEND-IA TNK study: EXTEND-IA TNK was designed to assess whether tenecteplase is non-inferior to alteplase in achieving reperfusion at initial angiogram when administered within 4.5 h of ischaemic stroke onset in patients planned to undergo endovascular therapy.
Patients with ischaemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy were randomised to receive tenecteplase 0.25 mg/kg or alteplase 0.9 mg/kg within 4.5 h after symptom onset. There were 101 patients in each treatment group. The primary outcome was reperfusion of greater than 50% of the involved ischaemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Noninferiority of tenecteplase was tested, followed by superiority. Secondary outcomes included the mRS score at 90 days.
The primary outcome occurred in 22% of the patients treated with tenecteplase vs 10% of those treated with alteplase (incidence difference, 12%; 95% CI 2, 21; incidence ratio, 2.2; 95% CI 1.1, 4.4; p=0.002 for non-inferiority; p=0.03 for superiority).
In an ordinal analysis of the modified Rankin scale score at 90 days, patients in the tenecteplase group had a median score of 2 (interquartile range, 0 to 3), which indicated significantly better function than the median score of 3 (interquartile range, 1 to 5) among patients in the alteplase group (common odds ratio, 1.7; 95% CI, 1.0 to 2.8; p=0.04). There was no significant difference in the incidence of recovery to independent function (modified Rankin scale score of 0 to 2 or no change from baseline function) at day 90, which occurred in 65 of 101 patients (64%) in the tenecteplase group and in 52 of 101 (51%) in the alteplase group (adjusted incidence ratio, 1.2; 95% CI, 1.0 to 1.5; p=0.06; adjusted odds ratio, 1.8; 95% CI, 1.0 to 3.4; p=0.06).
The proportion of mRS 0-1 at 90 days was 51% for the tenecteplase group and 43% for the alteplase group (p=0.23).
The sICH occurred in 1% of the patients in each group. There were 10 deaths (10%) in the tenecteplase group and 18 (18%) in the alteplase group, which was not significant in the pre-specified logistic-regression analysis. Most of the deaths were related to progression of major stroke (9 in tenecteplase group and 14 in alteplase group). Tenecteplase 0.25 mg/kg showed a similar safety profile compared to alteplase 0.9 mg/kg.
EXTEND-IA TNK Part 2 study: EXTEND-IA TNK Part 2 was designed to determine whether 0.4 mg/kg of tenecteplase safely improves reperfusion before endovascular thrombectomy vs 0.25 mg/kg of tenecteplase in patients with large vessel occlusion (LVO) ischaemic stroke.
Adult patients with ischaemic stroke due to occlusion of the intracranial internal carotid, basilar, or middle cerebral artery were included into the trial less than 4.5 h after symptom onset using standard iv thrombolysis eligibility criteria. Patients were randomly assigned (1:1) to receive the tenecteplase 0.25 mg/kg or 0.4 mg/kg. The primary outcome was reperfusion of greater than 50% of the involved ischaemic territory prior to thrombectomy, assessed by consensus of 2 blinded neuroradiologists.
The number of participants with more than 50% reperfusion of the previously occluded vascular territory was 29 of 150 (19.3%) in the 0.4 mg/kg group vs 29 of 150 (19.3%) in the 0.25 mg/kg group (unadjusted risk difference, 0.0% [95% CI -8.9%, 8.9%]; adjusted risk ratio (RR), 1.03 [95% CI 0.66, 1.61]; p=0.89). There were no significant differences in any of the 4 functional outcomes between the 0.4 mg/kg and 0.25 mg/kg groups nor in all-cause deaths (26 [17%] vs 22 [15%], unadjusted risk difference, 2.7% [95% CI -5.6%, 11.0%]).
The sICH occurred in 7 patients (4.7%) in the 0.40 mg/kg group and 2 patients (1.3%) in the 0.25 mg/kg group (unadjusted risk difference, 3.3% [95% CI, -0.5, 7.2]; risk ratio [RR], 3.50 [95% CI 0.74, 16.62]; p=0.12). There were 26 deaths (17%) in the 0.40 mg/kg tenecteplase group and 22 death (15%) in the 0.25 mg/kg tenecteplase group (adjusted RR, 1.27 [95% CI 0.77, 2.11]; p=0.35).
Real World Evidence: Several non-interventional studies compared tenecteplase (0.25 mg/kg) versus alteplase (0.9 mg/kg) in AIS with or without large vessel occlusion (LVO) within 4.5 hours after symptom onset. These observational studies reported adjusted (or propensity score matched) estimates, included in total >2,900 AIS patients (from studies with over 100 patients treated with tenecteplase), and reported a consistent similar or favourable safety and effectiveness profile of tenecteplase in comparison with intravenous alteplase. Endpoints measured included functional outcome (3-month mRS score), all-cause mortality, intracranial haemorrhage and symptomatic intracranial haemorrhage, rates of angioedema, door-to needle time, door-in-door out time, imaging-to-thrombolysis time, thrombolysis-to-puncture time, and onset-to-needle time.
Pharmacokinetics: Absorption and distribution: Tenecteplase is an intravenously administered, recombinant protein that activates plasminogen. Following i.v. bolus administration of 30 mg tenecteplase in patients with acute myocardial infarction, the initially estimated tenecteplase plasma concentration was 6.45±3.60 μg/mL (mean±SD). The distribution phase represents 31%±22% to 69%±15% (mean±SD) of the total AUC following the administration of doses ranges from 5 to 50 mg.
Data on tissue distribution were obtained in studies with radioactively labelled tenecteplase in rats. The main organ to which tenecteplase distributed was the liver. It is not known whether and to which extent tenecteplase binds to plasma proteins in humans. The mean residence time (MRT) in the body is approximately 1 h and the mean (±SD) volume of distribution at the steady-state (Vss) ranged from 6.3±2 L to 15±7 L.
Metabolism: Tenecteplase is cleared from the circulation by binding to specific receptors in the liver followed by catabolism to small peptides. Binding to hepatic receptors is, however, reduced compared to native t-PA, resulting in a prolonged half-life.
Elimination: After single intravenous bolus injection of tenecteplase in patients with acute myocardial infarction, tenecteplase antigen exhibits biphasic elimination from plasma. There is no dose dependence of tenecteplase clearance in the therapeutic dose range. The initial, dominant half-life is 24±5.5 (mean±SD) min, which is 5 times longer than native t-PA. The terminal half-life is 129±87 min, and plasma clearance is 119±49 ml/min.
Increasing body weight resulted in a moderate increase of tenecteplase clearance, and increasing age resulted in a slight decrease of clearance. Women exhibit in general lower clearance than men, but this can be explained by the generally lower body weight of women.
Linearity/Non-Linearity: The dose linearity analysis based on AUC suggested that tenecteplase exhibits non-linear pharmacokinetics in the dose range studied, i.e. 5 to 50 mg.
Special populations: Renal and hepatic impairment: Because elimination of tenecteplase is through the liver, it is not expected that renal dysfunction will affect the pharmacokinetics of METALYSE. This is also supported by animal data. However, the effect of renal and hepatic dysfunction on pharmacokinetics of tenecteplase in humans has not been specifically investigated.
Toxicology: Preclinical safety data: Intravenous single dose administration in rats, rabbits and dogs resulted only in dose-dependent and reversible alterations of the coagulation parameters with local haemorrhage at the injection site, which was regarded as a consequence of the pharmacodynamic effect of tenecteplase. Multiple-dose toxicity studies in rats and dogs confirmed these previously mentioned observations, but the study duration was limited to two weeks by antibody formation to the human protein tenecteplase, which resulted in anaphylaxis.
Safety pharmacology data in cynomolgus monkeys revealed reduction of blood pressure followed by transient changes of ECG but these occurred at exposures that were considerably higher than the clinical exposure.
With regard to the indication and the single dose administration in humans, reproductive toxicity testing was confined to the rabbit, as a sensitive species. Tenecteplase induced no teratogenicity. Repeated dose administration resulted in bleeding with secondary mortality of dams. In a few cases abortion and resorption of the foetus occurred. Effects were not seen after single dose administration of tenecteplase.
Mutagenicity and carcinogenicity are not expected for this class of recombinant proteins and genotoxicity and carcinogenicity testing were not necessary.
No local irritation of the blood vessel was observed after intravenous, intra-arterial or paravenous administration of the final formulation of tenecteplase.