Tenecteplase

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 a higher fibrin specificity and greater resistance to inactivation by its endogenous inhibitor (PAI-1) compared to native t-PA.

Pharmacodynamic effects

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.

Absorption and distribution

Tenecteplase is an intravenously administered, recombinant protein that activates plasminogen. Following intravenous 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.

Biotransformation

Tenecteplase is cleared from 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.

Renal and hepatic impairment

Because elimination of tenecteplase is through the liver, it is not expected that renal dysfunction will affect its the pharmacokinetics. 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. Accordingly, there is no guidance for the adjustment to tenecteplase dose in patients with hepatic and severe renal insufficiency.

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 above-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 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 limited to an embryotoxicity study in rabbits, as a sensitive species. Tenecteplase induced total litter deaths during the mid-embryonal period. When tenecteplase was given during the mid- or late-embryonal period maternal animals showed vaginal bleeding on the day after the first dose. Secondary mortality was observed 1-2 days later. Data on the foetal period are not available.

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.