Reteplase

Reteplase is a recombinant plasminogen activator that catalyzes the cleavage of endogenous plasminogen to generate plasmin. This plasminogenolysis occurs preferentially in the presence of fibrin. Plasmin in turn degrades fibrin, which is the main component of the matrix of thrombi, thereby exerting its thrombolytic action.

Reteplase (10 + 10 U) dose-dependently reduces plasma fibrinogen levels by about 60 to 80%. The fibrinogen level normalises within 2 days. As with other plasminogen activators a rebound phenomenon then occurs during which fibrinogen levels reach a maximum within 9 days and remain elevated for up to 18 days.

Reductions of plasma levels of plasminogen and α2-antiplasmin normalise within 1 to 3 days. Coagulation factor V, clotting factor VIII, α2-macroglobulin, and C1-esterase inhibitor are only slightly reduced and normalise within 1 to 2 days. Plasminogen activator inhibitor 1 (PAI-1) activity can be reduced to around zero, but rapidly normalises within two hours showing a rebound phenomenon. Prothrombin activation fragment 1 levels and thrombin-antithrombin III-complexes increase during thrombolysis indicating thrombin production of which the clinical relevance is unknown.

Elimination

Following intravenous bolus injection of 10 + 10 U in patients with acute myocardial infarction reteplase antigen is distributed in plasma with a dominant half-life (t½α) of 18 ± 5 min and eliminated with a terminal half-life (t½ß) of 5.5 hours ± 12.5 min at a clearance rate of 121 ± 25 ml/min. Reteplase activity is cleared from the plasma at a rate of 283 ± 101 ml/min, resulting in a dominant half-life (t½α) of 14.6 ± 6.7 min and a terminal half-life (t½ß) of 1.6 hours ± 39 min. Only minor amounts of reteplase were immunologically detected in the urine. Exact data on the main elimination routes for reteplase in humans are not available and the consequences of hepatic or renal insufficiency are not known. Experiments in rats indicate that the liver and the kidneys are the main organs of active uptake and lysosomal degradation.

Additional studies in human plasma samples in vitro suggest that complexation with C1-inactivator, α2-antiplasmin and α2-antitrypsin contributes to the inactivation of reteplase in plasma. The relative contribution of the inhibitors to inactivation of reteplase decreases as follows: C1-inactivator > α2- antiplasmin > α2-antitrypsin.

The half-life of reteplase was increased in patients with AMI as compared to healthy volunteers. An additional increase of half-life of activity in patients with myocardial infarction and severely impaired liver and renal function cannot be excluded, but no clinical data of pharmacokinetics of reteplase in these patients are available. Animal data show that in case of severely impaired renal function with a pronounced increase in serum creatinine and serum urea an increase in half-life of reteplase has to be expected. Mild impairment of renal function did not significantly affect the pharmacokinetic properties of reteplase.

Acute toxicity studies were performed in rats, rabbits and monkeys Subacute toxicity studies were performed in rats, dogs and monkeys. The predominant acute symptom after single high doses of reteplase in rats and rabbits was transient apathy shortly after injection. In cynomolgus monkeys, the sedative effect ranged from slight apathy to unconsciousness, caused by a reversible dose-related drop in blood pressure. There was increased local haemorrhage at the injection site.

Subacute toxicity studies did not reveal any unexpected adverse events. In dogs repeated dosing of the human peptide reteplase led to immunologic-allergic reactions. Genotoxicity of reteplase was excluded by a complete battery of tests at different genetic end points in vitro and in vivo.

Reproductive toxicity studies were performed in rats (fertility and embryo-foetotoxicity study including a littering phase) and in rabbits (embryo-foetotoxicity study, dose-range finding only). In rats, a species insensitive to the pharmacological effects of reteplase, there were no adverse effects on fertility, embryo-foetal development and offspring. In rabbits, vaginal bleedings and abortions possibly associated to prolonged haemostasis, but no foetal abnormalities were noted. A pre- and postnatal toxicity study was not performed with reteplase.