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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.

 

  • References

  • 1 Rosenberg RD. Biochemistry of heparin antithrombin interactions, and the physiologic role of this natural anticoagulant mechanism. Am J Med 1989; 87: 2S
    CrossrefPubMedGoogle Scholar
  • 2 Harker LA, Hanson SR. Experimental arterial thromboembolism in baboons: Mechanism, quantitation, and pharmacologic prevention. J Clin Invest 1979; 64: 559
    CrossrefPubMedGoogle Scholar
  • 3 The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990; 336: 827
    CrossrefPubMedGoogle Scholar
  • 4 Marder VJ, Soulen RL, Atichartakarn V, Budzynski AZ, Parulekar S, Kim JR, Edward N, Zahavi J, Algazy KM. Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med 1977; 89: 1018
    PubMedGoogle Scholar
  • 5 Bratt G, Tornebohm E, Gragvist S, Aberg W, Lockner D. A comparison between low molecular weight heparin (KABI 2165) and standard heparin in the intravenous treatment of deep vein thrombosis. Thromb Haemostas 1985; 54: 813
    PubMedGoogle Scholar
  • 6 Lane DA, Denton J, Flynn AM, Thunberg L, Lindahl U. Anticoagulant activities of heparin oligosaccharides and their neutralization by platelet factor 4. Biochem J 1984; 218: 725
    CrossrefPubMedGoogle Scholar
  • 7 Hogg PJ, Jackson CM. Fibrin monomer protects thrombin from inactivation by heparin-antithrombin III: Implications for heparin efficacy. Proc Natl Acad Sci USA 1989; 86: 3619
    CrossrefPubMedGoogle Scholar
  • 8 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385
    CrossrefPubMedGoogle Scholar
  • 9 Mirshahi M, Soria J, Soria C, Faivre F, Lu H, Courtney M, Roitsch C, Tripier D, Caen JP. Evaluation of the inhibition by heparin and hirudin of coagulation activation during rt-PA-induced thrombolysis. Blood 1989; 74: 1026
    PubMedGoogle Scholar
  • 10 Thaler E, Lechner K. Antithrombin III deficiency and thromboembolism. In: Clinics in Haematology, Vol 10. Prentice CRM. (ed). Philadelphia, PA, Saunders: 1981: 369
  • 11 Markwardt F. Biochemistry and pharmacology of hirudin. In: Hemostasis and Animal Venoms. Pirkle H, Markland FS. (eds). New York NY: Marcel Dekker; 1988: 255
  • 12 Maraganore JM, Bourdon P, Jablonski J, Ramachandran KL, Fenton JW. Design and characterization of hirulogs: A novel class of bivalent peptide inhibitors of thrombin. Biochemistry 1990; 29: 7095
    CrossrefPubMedGoogle Scholar
  • 13 Kelly AB, Maraganore JM, Bourdon P, Hanson SR, Harker LA. Antithrombotic effects of synthetic peptides targeting different functional domains of thrombin. Proc Natl Acad Sci USA 1992; 89: 6040
    CrossrefPubMedGoogle Scholar
  • 14 Klement P, Hirsh J, Maraganore J, Fenton J, Weitz J. Effects of heparin and hirulog on t-PA induced thrombolysis in a rat model. Thromb Haemostas 1992; 68: 64
    PubMedGoogle Scholar
  • 15 Mielke CH. International Committee Communications: Measurement of the bleeding time. Thromb Haemostas 1984; 52: 210
    PubMedGoogle Scholar
  • 16 Wagner JG. Fundamentals of Clinical Pharmacokinetics. Hamilton IL. Drug Intelligence Publications, Inc.; 1975. 1..
    Google Scholar
  • 17 Gibaldi M, Perrier D. Pharmacokinetics. New York, NY; Marcel Dekker, Inc.: 1982. 2..
    Google Scholar
  • 18 Harker LA, Slichter SJ. The bleeding time as a screening test for evaluation of platelet function. N Engl J Med 1972; 287: 155
    CrossrefPubMedGoogle Scholar
  • 19 Jakubowski JA, Stampfer MJ, Vaillancourt R, Deykin D. Cumulative antiplatelet effect of low-dose enteric coated aspirin. Br J Haematol 1985; 60: 635
    CrossrefPubMedGoogle Scholar
  • 20 Mann KG, Lundblad RJ. Biochemistry of thrombin. In: Hemostasis and Thrombosis, Basic Principles and Clinical Practice. Colman R, Hirsh J, Marder V, Salzman E. (eds) Philadelphia, PA: Lippincott; 1987: 148
    Google Scholar
  • 21 Fenton JW. Thrombin specificity. Ann NY Acad Sci 1981; 370: 468
    CrossrefPubMedGoogle Scholar
  • 22 Tollefsen DM, Feagler JR, Majerus PW. The binding of thrombin to the surface of platelets. J Biol Chem 1974; 249: 2546
    PubMedGoogle Scholar
  • 23 Chen LB, Buchanan JM. Mitogenic activity of blood components. I. Thrombin and prothrombin. Proc Natl Acad Sci USA 1975; 72: 131
    CrossrefPubMedGoogle Scholar
  • 24 Berk BC, Taubman MB, Cragoe EJ, Fenton JW, Griendling KK. Thrombin signal transduction mechanisms in rat vascular smooth muscle cells. J Biol Chem 1990; 265: 17334
    PubMedGoogle Scholar
  • 25 Markwardt F, Hauptmann J, Nowak G, Klessen C, Walsmann P. Pharmacological studies on the antithrombotic action of hirudin in experimental animals. Thromb Haemostas 1982; 47: 226
    PubMedGoogle Scholar
  • 26 Hanson SR, Harker LA. Interruption of acute platelet-dependent thrombosis by the synthetic antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone. Proc Natl Acad Sci USA 1988; 85: 3184
    CrossrefPubMedGoogle Scholar
  • 27 Kelly AB, Marzee UM, Krupski W, Bass A, Cadroy Y, Hanson SR, Harker LA. Hirudin interruption of heparin-resistant arterial thrombus formation in baboons. Blood 1991; 77: 1006
    PubMedGoogle Scholar
  • 28 Cadroy Y, Maraganore JM, Hanson SR, Harker LA. Selective inhibition by a synthetic hirudin peptide of fibrin-dependent thrombosis in baboons. Proc Natl Acad Sci USA 1991; 88: 1177
    CrossrefPubMedGoogle Scholar
  • 29 Nossel HL, Ti M, Kaplan KL, Spanondis K, Soland T, Butler Jr VP. The generation of fibrinopeptide A in clinical blood samples: Evidence for thrombin activity. J Clin Invest 1976; 58: 1136
    CrossrefPubMedGoogle Scholar
  • 30 Theroux P, Latour JG, Leger-Gauthier C, De Lara J. Fibrinopeptide A and platelet factor levels in unstable angina pectoris. Circulation 1987; 75: 156
    CrossrefPubMedGoogle Scholar
  • 31 Eisenberg PR, Sherman LA, Jaffe AS. Paradoxic elevation of fibrinopeptide A after streptokinase: Evidence for continued thrombosis despite intense fibrinolysis. J Am Coll Card 1987; 10: 527
    CrossrefPubMedGoogle Scholar
  • 32 Rapold HJ. Promotion of thrombin activity by simultaneous thrombolytic therapy without simultaneous anticoagulation. Lancet 1990; 335: 481
    PubMedGoogle Scholar
  • 33 Hirsh J. Heparin. N Engl J Med 1991; 324: 1565
    CrossrefPubMedGoogle Scholar
  • 34 Lindahl U, Hook M. Glucosaminoglycans and their binding to biological macromolecules. Annu Rev Biochem 1978; 47: 385
    CrossrefPubMedGoogle Scholar
  • 35 Glimelius B, Busch C, Hook M. Binding of heparin on the surface of cultured endothelial cells. Thromb Res 1978; 12: 773
    CrossrefPubMedGoogle Scholar
  • 36 Hull RD, Raskob GE, Hirsh J, Jay RM, Leclerc JR, Geerts WH, Rosenbloom D, Sackertt DL, Anderson C, Harrison L, Gent M. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the initial treatment of proximal vein thrombosis. N Engl J Med 1986; 315: 1109
    CrossrefPubMedGoogle Scholar
  • 37 McGarry T, Gottlieb R, Zelenkofske S, Duca P, Kasparian H, Kreulen T, Morganroth J. Relationship of anticoagulation level and complications after successful percutaneous transluminal coronary angioplasty (PTCA). Circulation 1990; 82: III-189 (abstr)
    PubMedGoogle Scholar
  • 38 Bicher J, Fichtl B, Silbeck M, Fritz H. Pharmacokinetics and pharmacodynamics of hirudin in man after single subcutaneous and intravenous bolus administration. Arzheim-Forsch/Drug Res 1988; 38: 704
    PubMedGoogle Scholar