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Thromb Haemost 1998; 79(01): 134-139
DOI: 10.1055/s-0037-1614232
Review Article
Schattauer GmbH

Pharmacokinetics of a Slower Clearing Tissue Plasminogen Activator Variant, TNK-tPA, in Patients with Acute Myocardial Infarction

Authors

  • Nishit B. Modi

    1   From the Departments of Pharmacokinetics and Metabolism, One DNA Way, S. San Francisco, CA, USA

  • Stephen Eppler

    1   From the Departments of Pharmacokinetics and Metabolism, One DNA Way, S. San Francisco, CA, USA

  • Judy Breed

    2   From the Departments of Medical Affairs, One DNA Way, S. San Francisco, CA, USA

  • Christopher P. Cannon

    3   Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical

  • Eugene Braunwald

    3   Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical

  • Ted W. Love

    4   From the Departments of Product Development, Genentech, Inc., One DNA Way, S. San Francisco, CA, USA
Further Information

Publication History

Received 01 March 1997

Accepted after resubmission 11 August 1997

Publication Date:
08 December 2017 (online)

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Summary

The rapid clearance of t-PA from plasma requires administration by intravenous (IV) infusion. A slower clearing, fibrin-specific rt-PA variant may allow single intravenous bolus administration, thereby simplifying dosing. This study was designed to characterize the pharmacokinetics of the slower clearing, fibrin-specific tissue-plasminogen activator variant, TNK-tPA, in patients with acute myocardial infarction (AMI) following a single IV bolus injection. Single IV bolus doses of 5 to 50 mg of TNK-tPA were studied in an open-label, multicenter, dose escalation study. A total of 113 AMI patients were enrolled. Blood sampling for pharmacokinetics was conducted in eighty-two patients (72 men, 10 women), with 5 to 27 patients per dose. TNK-tPA was administered as an IV bolus over 5–10 s. Following IV bolus administration, there was a biphasic elimination of TNK-tPA from plasma. The initial phase had a mean half-life that ranged from 11 ± 5 to 20 ± 6 min and was followed by a terminal phase with a mean half-life that ranged from 41 ± 16 to 138 ± 84 min. Mean TNK-tPA plasma clearance was 125 ± 25 - 216 ± 98 ml/min, and the initial volume of distribution was 4.3 ± 2 - 8.4 ± 6 l. A decrease in TNK-tPA plasma clearance with increasing TNK-tPA dose was noted. In addition, women and patients with lower body weight or older age had a slower plasma clearance. In conclusion, TNK-tPA has a slower plasma clearance in patients with AMI than that reported for rt-PA, allowing administration as a single IV bolus.