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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

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
› Author Affiliations
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.

 

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