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Thromb Haemost 1993; 69(02): 157-163
DOI: 10.1055/s-0038-1651573
Original Article
Heparin
Schattauer GmbH Stuttgart

Anticoagulant Activity of Hirulog™, a Direct Thrombin Inhibitor, in Humans

Irving Fox
1   The Medical Research, Biogen, Inc., Cambridge, MA, USA
,
Adrian Dawson
1   The Medical Research, Biogen, Inc., Cambridge, MA, USA
,
Peter Loynds
1   The Medical Research, Biogen, Inc., Cambridge, MA, USA
,
Jane Eisner
1   The Medical Research, Biogen, Inc., Cambridge, MA, USA
,
Kathleen Findlen
1   The Medical Research, Biogen, Inc., Cambridge, MA, USA
,
Elizabeth Levin
1   The Medical Research, Biogen, Inc., Cambridge, MA, USA
,
Don Hanson
2   The Bioassay, Biogen, Inc., Cambridge, MA, USA
,
Tim Mant
3   The Clinical Pharmacology Unit, Guy’s Hospital, London, England
,
John Wagner
4   The College of Pharmacy, the University of Michigan, USA
,
John Maraganore
5   The Thrombosis and Hemostasis Research Departments, Biogen, Inc., Cambridge, MA, USA
› Author Affiliations
Further Information

Publication History

Received 09 July 1992

Accepted after revision 13 October 1992

Publication Date:
03 July 2018 (online)

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Summary

Hirulog™ (BG8967) is a direct thrombin inhibitor built by rational design using the protein hirudin as a model (Maraganore et al. [1990]; Biochemistry 29: 7095–101). In order to evaluate the therapeutic potential for hirulog in the management of thrombotic disease, the tolerability and anticoagulant activity of the agent were examined in a study of human volunteers.

In a randomized, placebo-controlled study (n = 54), the intravenous infusion of hirulog over 15 min showed a rapid, dose-dependent prolongation of activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT). There was a corresponding dose-dependent increase in plasma hirulog levels. The peptide was rapidly cleared with a half-life of 36 min and a total body clearance rate for the peptide of 0.43 1 kg−1 h−1. Similar activity was observed following subcutaneous injection but with sustained pharmacodynamic and pharmacokinetic behavior. There was a significant correlation between pharmacokinetic and pharmacodynamic variables for both intravenous (r = 0.8, p <0.001) and subcutaneous administration (r = 0.7, p = 0.002).

To evaluate the possible interactions of aspirin on the tolerability and anticoagulant activity of intravenous hirulog, a cross-over design was employed in eight subjects. Aspirin administration did not modify the peptide’s activity. At the administered dose of 0.6 mg kg−1 h−1 for 2 h, hirulog infusion prolonged APTT from 230 to 260% baseline. The infusion of hirulog in subjects who had received aspirin was not associated with any significant changes in the template bleeding time.

The final phase of the study examined the activity and tolerability of hirulog in ten subjects during prolonged intravenous infusions for up to 24 h. The peptide (0.3 mg kg−1 h−1) exhibited sustained anticoagulant activity with no evidence for a cumulative effect. During hirulog infusion, APTT was prolonged from 210 to 250% baseline.

In all phases of the study, hirulog administration was generally well-tolerated.

Our observations show that hirulog is an active antithrombin agent with excellent tolerability in humans. As a direct thrombin inhibitor, hirulog provides a novel approach for the management of thrombotic disease.

 

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