Pharmacokinetics and Pharmacodynamics of Tenecteplase: Results from a Phase II Study in Patients with Acute Myocardial Infarction

Tenecteplase is a site‐specific engineered tissue plasminogen activator (t‐PA) variant that can be administered as a single intravenous bolus injection because of its slower plasma clearance. The objective of this study was to investigate the dose‐ranging pharmacokinetics and pharmacodynamics of intravenous bolus tenecteplase compared with intravenous alteplase recombinant t‐PA in patients with acute myocardial infarction. A total of 103 patients received intravenous bolus doses of 30, 40, or 50 mg tenecteplase, and 56 patients received 100 mg rt‐PA as the accelerated 90‐minute infusion regimen in this randomized, open‐label study. Tenecteplase and r‐tPA plasma concentrations were measured for 6 hours. Tenecteplase exhibited biphasic elimination from the plasma with a mean initial half‐life of 22 minutes and a mean terminal half‐life of 115 minutes. The mean plasma clearance was 105 mL/min and did not depend on tenecteplase dose over the dose range studied. In comparison, rt‐PA has a fourfold faster plasma clearance. Pharmacokinetic‐pharmacodynamic evaluation showed that a dose of approximately 0.5 mg/kg results in a plasma AUC value that provides a TIMI 3 flow at 90 minutes that is comparable to that reported with accelerated r‐tPA. In conclusion, tenecteplase has a fourfold slower plasma clearance compared with rt‐PA, allowing dosing as an W bolus injection. Weight‐adjusted dosing of tenecteplase may optimize the therapeutic regimen of tenecteplase.