Effect of a 15-Minute Infusion of DDAVP on the Pharmacokinetics and Pharmacodynamics of ™REVASC during a Four-Hour Intravenous Infusion in Healthy Male Volunteers

Dipti M Amin; Timothy G K Mant; Stephen M Walker; Roger Kerry; Peter Lloyd; Gilbert Lefèvre; Philippe Close

doi:10.1055/s-0038-1655919

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 1997; 77(01): 127-132
DOI: 10.1055/s-0038-1655919

Coagulation

Schattauer GmbH Stuttgart

Effect of a 15-Minute Infusion of DDAVP on the Pharmacokinetics and Pharmacodynamics of ™REVASC during a Four-Hour Intravenous Infusion in Healthy Male Volunteers

Authors

Dipti M Amin

¹The Guy's Drug Research Unit (GDRU Ltd), London
Timothy G K Mant

¹The Guy's Drug Research Unit (GDRU Ltd), London
Stephen M Walker

²The Ciba Pharmaceuticals, Horsham, UK
Roger Kerry

³The Ciba Phamaceuticais, Basel, Switzerland
Peter Lloyd

²The Ciba Pharmaceuticals, Horsham, UK
Gilbert Lefèvre

⁴The Laboratories Ciba-Geigy, Rueil-Malmaison, France
Philippe Close

³The Ciba Phamaceuticais, Basel, Switzerland

Abstract

als PDF herunterladen

Summary

Plasma pharmacokinetics, effect on coagulation parameters, and safety and tolerability of an intravenous infusion of ™REVASC before, during and after a DDAVP infusion were investigated.

Twelve healthy volunteers were given an intravenous bolus dose followed by a constant rate four-hour infusion of ™REVASC. Fifteen-minute infusions of 0.9% saline and DDAVP were started two and three hours respectively after the start of the ™REVASC infusion.

Plasma ™REVASC concentrations were not affected by either the saline or DDAVP infusion. ™REVASC infusion produced an increase in APTT which plateaued between 0.5 and 3 hours. After the DDAVP infusion there was a tendency towards a new lower plateau whilst the ™REVASC infusion continued. There were no serious adverse events or bleeding episodes throughout the study.

In conclusion, the co-administration of intravenous DDAVP has no effect on the plasma pharmacokinetics of ™REVASC and partially reverses the ™REVASC-induced increase in APTT. This may represent a role for DDAVP in the partial reversal of anticoagulation induced by ™REVASC.

PDF (1657 kb)

Referenzen

References
1 Johnson PH. Hirudin: Clinical potential of a thrombin inhibitor. Annu Rev Med 1994; 45: 165-177
2 Monreal M, Costa J, Salva P. Pharmacological properties of hirudin and its derivatives: potential clinical advantages over heparin. Drugs and Ageing 1996; Vol 08 No 3 171-82
3 Mezhack B, Heim J, Rink H, Zimmermann W, Maerki W. Desulfato- hirudin, a specific thrombin inhibitor; expression and secretion in yeast. Thromb Res. (supplement 07) 1987: 33
4 Grossenbacher H, Auden JAL, Bill K, Maerki WMaschler. Isolation and characterisation of recombinant desulphato-hirudin from yeast, a highly selective thrombin inhibitor. Thromb Res. (supplement 07) 1987: 34
5 Markwardt F, Hauptmann J, Brüggener E. Pharmacological studies on the antithrombotic action of hirudin in experimental animals. Thromb Haemost 1982; 47 (03) 226-229
6 Ishikawa A, Hafter R, Seemuller V, Gokel JM, Graeff H. The effects of hirudin on endotoxin induced disseminated intra-vascular coagulation (DIC). Thromb Res 1980; 19: 351-358
7 Markwardt F. Prevention of coronary thrombosis by hirudin. In: Cardiovascular Pharmacology. Papp JGy. (ed) 1987. pp 495-546
8 Hauptmann J, Bruggener E, Markwardt F. Effect of heparin, hirudin and a synthetic thrombin inhibitor on antithrombin II in thrombin-induced disseminated intra-vascular coagulation in rats. Haemostasis 1987; 17: 321-328
9 Talbot MD. Biology of recombinant hirudin (CGP 39 393): A new prospect in the treatment of thrombosis. Semin Thromb Haemostas 1989; Vol 15 No 3 293-301
10 Markwardt F. Development of hirudin as an antithrombotic drug. Thrombosis Research 1994; Vol 74 No.1 1-23
11 Markwardt F, Nowak G, Sturzebecher J, GrieBbach U, Walsmann P, Vogel G. Pharmacokinetics and anticoagulation effect of hirudin in man. Thromb Haemost 1984; 52: 160-163
12 Bichler J, Fichtl B, Siebeck M, Fichtl B. Pharmacokinetics and pharmacodynamics of hirudin in man after single subcutaneous and intravenous bolus administrations. Drug Res 1988; 38 I 704-710
13 Verstraete M, Nurmohamed M, Kienast J, Siebeck M, Silling-Engelhardt G, Büller H, Hoet B, Bichler J, Close P. Biologic effect of recombinant hirudin (CGP 39 393) in human volunteers. Journal of the American College of Cardiology 1993; Vol 22 No. 4 1080-1088
14 Bichler J, Siebeck M, Fichtl B, Fritz H. Pharmacokinetics, effect on clotting tests and assessment of the immunogenic potential of hirudin after a single subcutaneous or intravenous bolus administration in man. Haemostasis 1991; 21 (suppl) 137-141
15 Marbet GA, Verstraete M, Kienast J, Graf P, Hoet B, Tsakiris DA, Silling-Engelhardt G, Close P. Clinical pharmacology of intravenously administered recombinant desulfatohirudin (CGP 39 393) in healthy volunteers. Journal of Cardiovascular Pharm 1993; 22: 364-372
16 Schenk JF, Glusa E, Radizwon P, Butti A, Markwardt F, Breddin HK. A recombinant hirudin (IK-HIR02) in healthy volunteers. I. Effects on coagulation parameters and bleeding time. Haemostasis 1996; 26 (03) 140-149
17 Cannon CP, Braunwald E. Hirudin: Initial results in acute myocardial in farction, unstable angina and angioplasty. Journal of the American College of Cardiology 1995; Vol 25 No. 7 Suppl 30S-37S
18 Weitz JI, Hirsh J. New anticoagulants hirudin and hirulog in the treatment of acute conorary syndromes. Cardiology in Review 1995; Vol 03 No. 4 196-204
19 Fox KAA. Hirudin in unstable angina pectors. Rationale and preliminary data from the APT pilot study. European Heart Journal 1995; Vol 16 SupplD 28-32
20 Serruys PW, Herrman JPR, Simon R, Rutsch W, Bode C, Laarman GJ, Van-Dijk R, Van-den-Bos AA, Umans VAWN, Fox KAA, Close P, Deckers JW. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. New England Journal of Medicine 1995; 333 No. 12 757-763
21 Herrmann JPR, Simon R, Umans VAWN, Peerboom PF, Keane D, Runierse JJMM, Bach D, Kobi P, Kerry R, Close P, Deckers JW, Serruys PW. Evaluation of recombinant hirudin (CGP 39393/™REVASC) in the prevention of restenosis after percutaneous transluminal coronary angioplasty. Rationale and design of the HELVETICA trial, a multicentre randomised double blind heparin controlled study. European Heart Journal 1995; Vol 16 Suppl. L 56-62
22 Eriksson BI, Exman S, Kalebo P, Zachrisson B, Bach D, Close P. Prevention of deep vein thrombosis after total hip replacement: Direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996; Vol 347 No. 9002 635-639
23 Cofrancesco E, Cortellaro M, Leonardi P, Corradi A, Ravasi F, Bertocchi F. Markers of haemostatic system activation during thromboprophylaxis with recombinant hirudin in total hip replacement. Thromb Haemost 1996; 75 (03) 407-411
24 Williams DJ, Mahomed A, Eriksson BI. Hirudin CGP 39393 as thromboprophylaxis (19). Lancet 1996; 347 (9014) 1561-1562
25 Mannucci PM. Desmopressin (DDAVP) for treatment of disorders of haemostasis. Prog in Haemostasis and Thrombosis 1986; 19-45
26 Berntrup E. The treatment of haemophilia, including prophylaxis, constant infusion and DDAVP. Bailliere’s Clinical Haematology 1996; 09 (02) 259-271
27 Mannucci PM, Cattaneo M. Desmopressin: A non-transfusional treatment of haemophilia and von Willebrand Disease. Haemostasis 1992; 22: 276-280
28 David J. Desmopressin and haemostasis. Regulatory Peptides 1993; 45: 311-317
29 Lusher JM. Response to DDAVP in von Willebrand Disease. Haemostasis 1994; 24: 276-284
30 Derkay CS, Werner E, Plotnick E. Management of children with von Willebrand disease undergoing adenotonsillectomy. American Journal of Otolaryngology-Head and Neck Medicine and Surgery 1996; 17 (03) 172-177
31 MacGregor IR, Roberts EM, Prowse CV, Broomhead AF, Ozolins M, Litka P. Fibrinolytic and haemostatic responses to desamino-d-arginine vasopressin (DDAVP) adminstered by intravenous and subcutaneous routes in healthy subjects. Thromb Haemost 1988; 59 (01) 34-39
32 Mannucci PM. Desmopressin: A nontransfusional form of treatment for congenital and acquired bleeding disorders. Blood 1988; 72: 1449-1455
33 Kim HC, Salva K, Fallot PL, Karp GI, Eisele J, Matts L, Heller I, Saidi P. Patients with prolonged bleeding time of undefined etiology and their responses to desmopressin. Thromb Haemost 1988; 59 (02) 221-224
34 Casonato A, Pontara E, Bertomoro A, Zucchetto A, Zerbinati A, Girolami A. On the discrepant post-DDAVP increase of FVIII: C and von Willebrand factor in some patients with severe von Willebrand’s disease (2). British Journal of Haematology 1995; 91 (02) 512-513
35 Beck KH, Bleckmann U, Mohr P, Kretschmer V. DDAVP’s shortening of the bleeding time seems due to plasma von Willebrand factor. Seminars in Thrombosis and Haemostasis 1995; 21 (Suppl. 02) 40-43
36 DiMichele DM, Hathaway WME. Use of DDAVP in inherited and acquired platelet dysfunction Am J Haematol. 1990; 33: 39-45
37 Mckeown LP, Connaghan G, Wilson O, Hansmann K, Merryman P, Gralnick HR. l-Desamino-8-arginine-vasopressin corrects the haemostatic defects in type 2B von Willebrands disease. American Journal of Hematology 1996; 51 (02) 158-163
38 Rao AK, Ghosh S, Sun L, Disa J, Pickens P, Polansky M. Mechanisms of platelet dysfunction and response to DDAVP in patients with congenital platelet function defects – a double blind placebo controlled trial. Thromb Haemost 1995; 74 (04) 1071-1078
39 Janssen MJFMM, Van-der-Meulen J. The bleeding risk in chronic haemodialysis: preventive strategies in high risk patients. Netherlands Journal of Medicine 1996; Vol 48 No. 5 198-207
40 Agnelli G, Parise P, Levi M, Cosmi B, Nenci GG. Effects of desmopressin on hemostasis in patients with liver cirrhosis. Haemostasis 1995; 25 (05) 241-247
41 Schulam S, Johnsson H. Heparin, DDAVP and the bleeding time. Thromb Haemost 1991; 65 (03) 242-244
42 Schiele F, Vuillemenot A, Kramarz P, Kieffer Y, Anguenot T, Bernard Y, Bassand JP. Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia. American Journal of Haematology 1995; 50 (01) 20-25
43 Schiele F, Vuillemenot A, Mouhat T, Kieffer Y, Anguenot T, Bernard Y, Bassand JP. Recombinant hirudin anticoagulation in patients with heparin- induced thrombocytopenia. Presse Medicale 1996; 25 (16) 757-760
44 Lethagen S, Rugam P. The effect of DDAVP and placebo on platelet function and prolonged bleeding time induced by oral acetylsalicylic acid intake in healthy volunteers. Thromb Haemost 1992; 67 (01) 185-186
45 Mannuci PM, Lusher JM. Desmopressin and thrombosis. Lancet 1989; 02: 675
47 Cattaneo M, Harris AS, Stromberg U, Mannucci PM. The effects of desmopressin on reducing blood loss in cardiac surgery – a meta-analysis of double-blind, placebo controlled trials. Thromb Haemost 1995; 74 (04) 1064-1070
48 Clagett GP, Valentine RJ, Myers SI, Chervu A, Heller JA. Does desmopressin improve hemostasis and reduce blood loss from aortic surgery – a randomised, double blind study. Journal of Vascular Surgery 1995; 22 (03) 223-230
49 Butler KD, Dolan SL, Talbot MD, Wallis RB. Factor VIII and DDAVP reverse the effect of recombinant desulphatohirudin (CGP 39 393) on bleeding in the rat. Blood Coagulation & Fibrinolysis 1994; 04: 459-464
50 Bove CM, Casey B, Marder VJ. DDAVP reduces bleeding during continued hirudin administration in the rabbit. Thromb Haemost 1996; 03: 471-475
51 Ibbotson SH, Grant PJ, Kerry R, Findlay VS, Prentice CRM. The influence of infusions of DDAVP in vivo on the anticoagulant effect of recombinant hirudin in vitro. Throm Haemost 1991; 65 (01) 64-66
52 Schlaeppi JM, Vekemans S, Rink H, Chang JY. Preparation of monoclonal antibodies to hirudin and hirudin peptides. Eur J Biochem 1990; 188: 463-470
53 Spinner S, Stoffle G, Fink E. Quantitative enzyme-linked immunosorbent assay (ELISA) for hirudin. J Immunol Methods 1986; 87: 79-83
54 Biggs R, Rizza C. Human Blood Coagulation. Haemostasis and Thrombosis. 03. rd ed Blackwell Scientific Publications; Oxford, England: 1984
55 Richardson JH, Barkley WE. (eds) Biosafety in microbiological and biomedical laboratories. US Department of Health and Human Services, Public Health Service HHS Publication No. (CDC)84-8395 Washington, DC: 1984
56 Zucker S. et al Preparation of quality control specimen for coagulation. Am J Clin Pathol 1970; 53: 924-927
57 National Committee for Clinical Laboratory Standards H28P and H29P Proposed guidelines for the one stage prothrombin time and activated partial thromboplastin time tests (APTT). Villanova, PA: 1982
58 Triplet DA. Laboratory evaluation of coagulation. American Society of Clinical Pathology Press, Chicago, IL: 1982
59 British National Formulary. 1995: 311-312
60 Von-Gontard A, Lehmkuhl G. Desmopressin side effects. Journal of the American Academy of Child and Adolescent Psycharity 1996; Vol 35 No 2 129-30
61 Close P, Bichler J, Kerry R, Ekman S, Bueller HR, Kienast J, Marbet GA, Schramm W, Verstraete M. Weak allergenicity of recombinant hirudin CGP 39 393 (™REVASC) in immunocompetent volunteers. Coronary Artery Disease 1994; 05: 943-949