Pharmacokinetics and pharmacodynamics of tenecteplase: results from a phase II study in patients with acute myocardial infarction

• Published in: Journal of clinical pharmacology Vol. 40; no. 5; p. 508
• Main Authors: Modi, N B, Fox, N L, Clow, F W, Tanswell, P, Cannon, C P, Van de Werf, F, Braunwald, E
• Format: Journal Article
• Language: English
• Published: England 01.05.2000
• Subjects: Adult; Age Factors; Aged; Aged, 80 and over; Area Under Curve; Body Weight; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents - pharmacokinetics; Humans; Infusions, Intravenous; Injections, Intravenous; Male; Metabolic Clearance Rate; Middle Aged; Myocardial Infarction - drug therapy; Myocardial Infarction - metabolism; Tenecteplase; Tissue Plasminogen Activator - blood; Tissue Plasminogen Activator - pharmacokinetics
• ISSN: 0091-2700
• DOI: 10.1177/00912700022009125

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 i.v. bolus injection. Weight-adjusted dosing of tenecteplase may optimize the therapeutic regimen of tenecteplase.