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DOI: 10.1055/s-0038-1656077
Pharmacodynamic and Safety Results of PEG-Hirudin in Healthy Volunteers
Publication History
Received 30 July 1996
Accepted after revision 13 January 1997
Publication Date:
11 July 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199705/lookinside/thumbnails/10-1055-s-0038-1656077-1.jpg)
Summary
PEG-Hirudin, a chemically defined conjugate of recombinant hirudin and two molecules of polyethylene glycol (PEG)-5000 is a highly selective direct thrombin inhibitor with a significantly longer duration of action than non-conjugated recombinant hirudin permitting once daily subcutaneous administration. A series of placebo-controlled, randomized, Phase I clinical trials were conducted in 75 healthy volunteers to investigate the anticoagulant effects, safety and pharmacodynamics of PEG-Hirudin when administered intravenously as a bolus injection, infusion, and subcutaneously. After single i.v. injections of various doses of PEG-Hirudin (0.03-0.3 mg/kg) dose-dependent increases in anti-IIa activity and APTT were observed. Four hours after injection of 0.3 mg/kg, mean plasma concentration expressed in terms of anti-IIa activity was still 0.89 µg/ml, corresponding to a 1.8-fold prolongation of APTT. Continuous intravenous infusions of 0.01 and 0.02 mg/kg/h PEG-Hirudin resulted in maximum anti-IIa activities of 0.42 µg/ml and 0.77 µg/ml, respectively, at the end of a six-hour infusion period without having reached steady state at this time. After termination of the infusion, anticoagulant activity displayed an immediate exponential decrease. The anticoagulant activities of single subcutaneous doses of 0.05 to 0.6 mg/kg were studied in a further series of investigations and slow increases and prolonged durations of anti-IIa activity and APTT prolongation were found. Repeated, once daily subcutaneous administrations of 0.2 to 0.4 mg/kg for five days resulted in dose-dependent prolongations of APTT and increases in anti-IIa activity without completely reaching steady state conditions. In a further study, 0.3 mg/kg of PEG-Hirudin was given as an i.v. bolus injection followed by three repeated single daily s.c. injections. In this trial, the APTT was shorter than expected from previous studies; therefore, a direct comparison of various APTT reagents was made in the intravenous infusion trial. Of the APTT reagents tested, BioMérieux Silimat and IL-ellagic acid proved to be the most sensitive to PEG- Hirudin. The hirudin derivative PEG-Hirudin was. tolerated very well without immuno-allergic side effects. In view of the significantly prolonged anticoagulant efficacy in comparison to non-conjugated r-hirudin, PEG-Hirudin is a promising compound especially for repeated once daily subcutaneous administration.
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References
- 1 Walsmann P, Markwardt F. On the isolation of the thrombin inhibitor hirudin. Thromb Res 1985; 40: 563-569
- 2 Markwardt F, Hauptmann J, Nowak G, Kleβen Ch, Walsmann P. Pharmacological studies on the antithrombotic action of hirudin in experimental animals. Thromb Haemost 1982; 47: 226-229
- 3 Ishikawa A, Hafter R, Seemüller U, Gokel JM, Graeff H. The effect of hirudin on endotoxin induced disseminated intravascular coagulation (DIC). Thromb Res 1980; 19: 351-358
- 4 Rübsamen K, Eschenfelder V. Effect of recombinant hirudin (LU 52 369) on reocclusion rates after thrombolysis in rabbits. Haemostasis 1991; 21 (Suppl): 93-98
- 5 Weitz JI, Califf RM, Ginsberg JS, Hirsh J, Théroux P. New antithrombotics. Chest 1995; 108 (04) 471S-485S
- 6 Eriksson BJ, Ekman S, Kälebo P, Zachrisson B, Bach D, Close P. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39 393. Lancet 1996; 347: 635-639
- 7 Moia M, Schiele F, Walker M, Erikkson H, Camez A, Lemarie JC. Treatment of acute deep vein thrombosis (DVT) by subcutaneous r-hirudin (HBW 023): a multicenter Study. Thromb Haemost 1995; 73 (06) 1456
- 8 Iyer L, Shavit J, Koza M, Calabria R, Moran S, Fareed J. Alteration of pharmacokinetics and pharmacodynamics of recombinant hirudin (rHV 2-Lys 47) after repeated intravenous administration in dogs. Thromb Res 1993; 69: 59-70
- 9 Markwardt F. The development of hirudin as an antithrombotic drug. Thromb Res 1994; 74: 01-23
- 10 Esslinger H-U, Greger G, Lassmann A, Maurer R. General tolerability and effects on clotting parameters after single i.v. and s.c. bolus administration of recombinant hirudin (LU 52369) in man. Thromb Haemost 1991; 65 (06) 1291
- 11 Markwardt F, Richter M, Walsmann P, Riesener G, Paintz M. Preparation of dextran-bound recombinant hirudin and its pharmacokinetic behaviour. Biomed Biochim Acta 1990; 49: 1103-1108
- 12 Iorio A, Agnelli G, Leone M, Melelli P, Renga C, Nenci GG. Hirudin and PEG-Hirudin inhibit clot-bound thrombin more efficaciously than heparin. Ann Hematol 1993; 66 (Suppl. 01) 1818
- 13 Homberger W, Rübsamen K, Schweden J. Prolonged antithrombotic action of a new polyethyleneglycol-coupled hirudin (LU 57291) in two rat thrombosis models. Ann Hematol 1993; 66 (Suppl. 01) 20
- 14 Laux V, Schweden J, Maurer R, Homberger W, Rübsamen K. Antithrombotic effect of a new polyethyleneglycol-coupled hirudin (LU 57291) in a venous thrombosis model in the rabbit. Correlation with anti-factor Ha activity in plasma. Ann Hematol 1993; 66 (Suppl. 01) 27
- 15 Rübsamen K, Homberger W, Laux V, Schwarz M, Schweden J. Antithrombotic efficacy of the polyethyleneglycol-coupled hirudin mutein LU 57291 in experimentally induced venous and arterial thrombosis. Thromb Haemost 1993; 69: 2717
- 16 Folts JD, Crowell EB, Rowe GG. Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 1976; 54: 365-370
- 17 Kirchengast M, Rübsamen K. Prevention by PEG-Hirudin of platelet dependent thrombin formation in the stenosed, locally injured canine coronary artery. J Invasive Cardiol 1995; 7: C9
- 18 Walenga JM, Terrell MR, Koza MJ, Khenkina Y, Fareed J, Pifarré R. PEG-Hirudin as anticoagulant in cardiopulmonary bypass. Blood 1994; 84 (Suppl. 01) 72
- 19 Walenga JM, Terrell MR, Koza MJ, Khenkina Y, Fareed J, Pifarré R. PEG-Hirudin as anticoagulant in cardiopulmonary bypass. Thromb Haemost 1995; 73 (06) 1454
- 20 Zawilska K, Zozulinska M, Turowiecka Z, Blauhut M, Drobnik L, Vinazzer H. The effect of a long-acting recombinant hirudin (PEG-Hirudin) on experimental disseminated intravascular coagulation (DIC) in rabbits. Thromb Res 1993; 69: 315-420
- 21 Rübsamen K, Hornberger W. Prevention of early reocclusion after thrombolysis of copper coil-induced thrombi in the canine carotid artery: comparison of PEG-Hirudin and unfractionated heparin. Thromb Haemost 1996; 76 (01) 105-110
- 22 Spannagl M, Bichler J, Birg A, Lill H, Schramm W. Development of a chromogenic substrate assay for the determination of hirudin in plasma. Blood Coagulation Fibrinolysis 1991; 2: 121-127
- 23 Duke WW. The reaction of blood platelets to hemorrhagic disease. Description of a new method for determining the bleeding time and coagulation time and report of three cases of hemorrhagic diseases relieved by transfusion. JAMA 1910; 55: 1185-1192
- 24 Mielke C, Kaneshiro M, Nahler J, Weiner J, Rapaport S. The standardised normal Ivy bleeding time and its prolongation by aspirin. Blood 1969; 34: 204-215
- 25 Thomann P. Non-Compartmental Analysis Methods Manual. In: TopFit: Version 2.0; pharmacokinetic and pharmacodynamic data analysis for the PC. Heinzel G, Woloszczak R, Thomann P. eds. Gustav Fischer Verlag. Stuttgart Jena; New York: 1993. 2. 65-66
- 26 Aronson JK, Dengler HJ, Dettli L, Follath F. Standardization of symbols in clinical pharmacology. Eur J Clin Pharmacol 1988; 35: 1-7
- 27 Veng-Pedersen P, Gillespie WR. A polyexponential deconvolution method. Evaluation of the “gastrointestinal bioavailability” and mean in vivo dissolution time of some ibuprofen dosage forms. J Pharmacokinet Biopharm 1985; 13: 289-307
- 28 Hornberger W, Kluge M, Rübsamen K. No evidence for rebound activation of platelets and coagulation after long-term administration of PEG-Hirudin (LU 57291) in rats. Ann Hematol 1994; 68 (Suppl. 02) A100
- 29 Tripodi A, Chantarangkul V, Arbini AA, Moia M, Mannucci PM. Effects of hirudin on activated partial thromboplastin time determined with ten different reagents. Thromb Haemost 1993; 70 (02) 286-288