Tenecteplase TNKtPA

Tenecteplase, a genetically engineered t-PA, was assessed for pharmokinetics, safety, and efficacy in humans in the Thrombolysis in Myocardial Infarction 10A (TIMI 10A) trial.66 It was administered over 5-10 s as a single bolus of 5-50 mg and had a half-life of 17 min, nearly five times longer than t-PA.

Subsequently, the TIMI 10B trial, a phase II dosing trial,67 was carried out to identify a specific bolus dosing regimen of TNK-t-PA that would achieve similar rates of TIMI-3 flow on 90-min angiography as t-PA, with a similar safety profile. Patients were randomized after 12 h of symptom onset and given either a bolus dose of 30 or 50 mg of TNK or a front-loaded regimen of t-PA. The 50 mg arm was changed to 40 mg due to a high incidence of intracranial hemorrhage. The results showed 50 and 40 mg of TNK had a similar rate of TIMI-3 flow when compared to t-PA. No differences in mortality and reinfarction were observed.

The Assessment of the Safety of a New Thrombolytic: TNK-t-PA (ASSENT-1) trial, a phase II dose-ranging trial, was conducted in conjunction with the TIMI 10B trial to test the clinical safety of three doses of tenecteplase-tissue plasminogen activator (TNK-t-PA) in ST-elevation myocardial infarction.68 Doses of 30, 40, and 50 mg of TNK-t-PA i.v. bolus were selected. As discussed above, the 50 mg arm was discontinued. Overall, the safety profile of TNK-t-PA was similar to that of alteplase and no difference in incidence of total stroke, intracranial hemorrhage, severe bleeding, or death was observed among treatment groups.

Findings from the TIMI 10B and ASSENT-1 trials served as the basis for comparing TNK versus accelerated t-PA in the ASSENT-2 trial. In the ASSENT-2 trial patients were randomized to weight-adjusted single doses of TNK-t-PA or accelerated t-PA.69 No difference in mortality was noted at 30 days nor was there a difference in the rate of stroke and intracerebral hemorrhage. Thus, TNK-t-PA was equivalent to t-PA in terms of its 30-day mortality benefit. Mortality at 1 year remained unchanged between the two agents.70 However, for those treated with TNK-t-PA 4 h after the onset of symptoms, mortality at 30 days and 1 year was lower compared to t-PA.

In 2001, tenecteplase's efficacy was assessed with a GP IIb/IIIa inhibitor in the ASSENT-3 trial, a randomized trial that compared the efficacy and safety of tenecteplase plus enoxaparin or abciximab with that of tenecteplase plus weight-adjusted unfractionated heparin (UFH) in patients with AMI.71 The tenecteplase plus enoxaparin or abciximab regimens reduced the frequency of ischemic complications in AMI patients. The combination of tenecteplase with enoxaparin was more efficacious than tenecteplase with heparin, and there was no increase in the risk of bleeding or intracranial hemorrhage, even in patients over the age of 75. In contrast, while efficacy was improved with the combination of tenecteplase plus abciximab, this was offset by a doubling in the rate of major hemorrhage and a higher event rate in patients over the age of 75 and in diabetic patients. Therefore, it was concluded that tenecteplase plus enoxaparin was a viable alternative regimen to tenecteplase plus UFH for the treatment of ST-elevation AMI.

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