Download PDF
Thromb Haemost 1989; 61(03): 497-501
DOI: 10.1055/s-0038-1646622
Original Article
Schattauer GmbH Stuttgart

Pharmacokinetics and Haemostatic Status During Consecutive Infusions of Recom binant Tissue-Type Plasminogen Activator in Patients with Acute Myocardial Infarction

E Seifried
1   The Abteilungen.III and IV, Medizinische Klinik und Poliklinik der Universität Ulm, FRG
,
P Tanswell
2   Dr. Karl Thomae GmbH, Biberach, FRG
,
D Ellbrück
1   The Abteilungen.III and IV, Medizinische Klinik und Poliklinik der Universität Ulm, FRG
,
W Haerer
1   The Abteilungen.III and IV, Medizinische Klinik und Poliklinik der Universität Ulm, FRG
,
A Schmidt
1   The Abteilungen.III and IV, Medizinische Klinik und Poliklinik der Universität Ulm, FRG
› Author Affiliations
Further Information

Publication History

Received 30 September 1988

Accepted after revision 03 March 1989

Publication Date:
24 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

Pharmacokinetics and systemic effects of recombinant tissue type plasminogen activator (rt-PA) were determined during coronary thrombolysis in 12 acute myocardial infarction patients using a consecutive intravenous infusion regimen. Ten mg rt-PA were infused in 2 minutes resulting in a peak plasma concentration (mean ±SD) of 3310±950 ng/ml, followed by 50 mg in 1 h and 30 mg in 1.5 h yielding steady state plasma levels of. 2210±470 nglml and 930±200 ng/ml, respectively. All patients received intravenous heparin. Total clearance of rt-PA was 380±74 ml/min, t,½α was 3.6±0.9 min and t,½β was 16±5.4 min.

After 90 min, in plasma samples containing anti-rt-PA-IgG to inhibit in vitro effects, fibrinogen was decreased to 54%, plasminogen to 52%, α2-antiplasmin to 25%, α2-macroglobulin to 90% and antithrombin III to 85% of initial values. Coagulation times were prolonged and fibrin D-dimer concentrations increased from 0.40 to 2.7 μg/ml. It is concluded that pharmacokinetics of rt-PA show low interpatient variability and that its short mean residence time in plasma allows precise control of therapy. Apart from its moderate effect on the haemostatic system, rt-PA appears to lyse a fibrin pool in addition to the coronary thrombus.

Keywords

rt-PA - Myocardial infarction - Pharmacokinetics - Systemic haemostasis
 

  • References

  • 1 Sobel BE, Collen D, Grossbard EB. (eds) Tissue Plasminogen Activator in Thrombolytic Therapy. Marcel Dekker Inc; New York: 1987
    Google Scholar
  • 2 Guerci AD, Gerstenblith G, Brinker JA, Chandra NC, Gottlieb SO, Bahr RD, Weiss JL, Shapiro EP, Flaherty JT, Bush DE, Chew PH, Gottlieb SH, Halperin HR, Ouyang P, Walford GD, Bell WR, Fatterpaker AK, Llewellyn M, Topol EJ, Healy B, Siu CO, Becker LC, Weisfeldt ML. A randomized trial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent randomisation to elective coronary angioplasty. N Engl J Med 1987; 317: 1613-1618
    CrossrefPubMedGoogle Scholar
  • 3 Simoons ML, Betriu A, Col J, von Essen R, Lubsen J, Michel PL, Rutsch W, Schmidt W, Thery C, Vahanian A, Willems GM, Arnold AE R, de Bono DP, Dougherty FC, Lamberts H, Meier B, Raynaud P, Sanz GA, Serruys PW, Uebis R, van de Werf F, Wood D, Verstraete M. Thrombolysis with tissue type plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty. Lancet 1988; 197-203
    PubMedGoogle Scholar
  • 4 Baughman R. Pharmacokinetics of tissue plasminogen activator. In: Tissue Plasminogen Activator in Thrombolytic Therapy. Sobel BE, Collen D, Grossbard EB. (eds) Marcel Dekker Inc; New York: 1987. pp 41-53
    Google Scholar
  • 5 Garabedian HD, Gold HK, Leinbach RC, Yasuda T, Johns JA, Collen D. Dose-dependent thrombolysis, pharmacokinetics and hemostatic effects of recombinant human tissue-type plasminogen activator for coronary thrombosis. Am J Cardiol 1986; 58: 673-679
    CrossrefPubMedGoogle Scholar
  • 6 Garabedian HD, Gold HK, Leinbach RC, Johns JA, Yasuda T, Kanke M, Collen D. Comparative properties of two clinical preparations of recombinant tissue type plasminogen activator in patients with acute myocardial infarction. J Am Coll Cardiol 1987; 9: 599-607
    CrossrefPubMedGoogle Scholar
  • 7 Tiefenbrunn AJ, Graor RA, Robison AK, Lucas FV, Hotchkiss AH, Sobel BE. Pharmacodynamics of tissue-type plasminogen activator characterized by computer-assisted simulation. Circulation 1986; 73: 1291-1299
    CrossrefPubMedGoogle Scholar
  • 8 Stump DC, Topol EJ, Chen AB, Hopkins A, Collen D. Monitoring of haemostasis parameters during coronary thrombolysis with recombinant tissue-type plasminogen activator. Thromb Haemostas 1988; 59: 133-137
    PubMedGoogle Scholar
  • 9 Seifried E, Tanswell P. Comparison of specific antibody, D-Phe-Pro-Arg-CH2C1 and aprotinin for prevention of in vitro effects of recombinant tissue-type plasminogen activator on haemostasis parameters. Thromb Haemostas 1987; 58: 921-926
    PubMedGoogle Scholar
  • 10 Clauss A. Gerinnungsphysiologische Schnellmethode zur Bestimmung des Fibrinogens. Acta Haematol 1957; 17: 237-246
    CrossrefPubMedGoogle Scholar
  • 11 Stötzer KE, Amiral J, Spanuth E. Neue Methoden zur spezifischen Bestimmung von Fibrinspaltprodukten (D-Dimere). Lab Med 1988; 12: 51-59
    PubMedGoogle Scholar
  • 12 Merskey C, Lalezary P, Johnson AJ. A rapid, simple, sensitive method for measuring fibrinolytic split products in human serum. Proc Soc Exp Biol Med 1969; 131: 871-875
    CrossrefPubMedGoogle Scholar
  • 13 Seifried E, Tanswell P, Rijken DC, Barrett-Bergshoeff MM, Su CA P F, Kluft C. Pharmacokinetics of antigen and activity of recombinant tissue-type plasminogen activator after infusion in healthy volunteers. Arzneim-Forsch/Drug Res 1988; 3: 418-421
    PubMedGoogle Scholar
  • 14 Heinzel G. Curve fitting programs. In: Pharmacokinetics During Drug Development. Bozler G, van Rossum SM. (eds) Fischer; Stuttgart: 1982. p 207
    Google Scholar
  • 15 Boxenbaum HG, Riegelman S, Elashoff RM. Statistical estimations in pharmacokinetics. J Pharmacokinet Biopharm 1974; 2: 123-148
    CrossrefPubMedGoogle Scholar
  • 16 Gibaldi M, Perrier G. Pharmacokinetics, Ch. 2. Marcel Dekker; New York: 1982
    Google Scholar
  • 17 Mueller HS, Rao AK, Forman SA. the TIMI investigators. Thrombolysis in myocardial infarction (TIMI): comparative studies of coronary reperfusion and systemic fibrinogenolysis with two forms of recombinant tissue-type plasminogen activator. J Am Coll Cardiol 1987; 10: 479-490
    CrossrefPubMedGoogle Scholar
  • 18 Gold HK, Leinbach RC, Garabedian HD, Yasuda T, Johns J, Grossbard EB, Palacios I, Collen D. Acute coronary reocclusion after thrombolysis with recombinant human tissue-type plasminogen activator: prevention by a maintenance infusion. Circulation 1986; 73: 347
    CrossrefPubMedGoogle Scholar
  • 19 Verstraete M, Su CA P F, Tanswell P, Feuerer W, Collen D. Pharmacokinetics and effects on fibrinolytic and coagulation parameters of two doses of recombinant tissue-type plasminogen activator in healthy volunteers. Thromb Haemostas 1986; 56: 1-5
    PubMedGoogle Scholar
  • 20 Seifried E, Tanswell P, Rijken DC, Kluft C, Hoegee E, Nieuwenhuizen W. Fibrin degradation products are not specific markers for thrombolysis in myocardial infarction. Lancet 1987; 8554: 333-334
    PubMedGoogle Scholar
  • 21 Hajjar KA, Hamel NM, Harpel PC, Nachman RL. Binding of tissue type plasminogen activator to cultured human endothelial cells. J Clin Invest 1987; 80: 1712-1719
    CrossrefPubMedGoogle Scholar
  • 22 Eisenberg PR, Sherman LA, Tiefenbrunn AJ, Ludbrook PA, Sobel BE, Jaffe AS. Sustained fibrinolysis after administration of t-PA despite its short half-life in the circulation. Thromb Haemostas 1987; 57: 35-40
    PubMedGoogle Scholar
  • 23 Krause J. Catabolism of tissue type plasminogen activator (t-PA), its variants, mutants and hybrids. Fibrinolysis 1988; 2: 133-142
    PubMedGoogle Scholar
  • 24 Seifried E, Bock F, Tanswell P, Rijken DC, Kluft C, Heimpel H. Rekombinanter Gewebe-Plasminogen-Aktivator: Pharmakokinetik und Wirkungen auf das Hamostasesystem des Menschen. Klin Wochenschr 1988; 66 Suppl (Suppl. 07) 40-49
    PubMedGoogle Scholar
  • 25 Seifried E, Tanswell P, Su CA P F, Feuerer W, Rijken DC, Kluft C. Dose linearity and differentiation of in vitro and in vivo effects of rt-PA on haemostatic parameters in healthy men. Fibrinolysis 1988; 2 Suppl (Suppl. 01) 81
    PubMedGoogle Scholar
  • 26 Kluft C, Los P, Jie AF H, van Hinsberg VW M, Vellenja E, Jespersen J, Henny CL P. The mutual relationship between the two molecular forms of the major fibrinolysis inhibitor a2-antiplasmin in the blood. Blood 1986; 67: 616-622
    PubMedGoogle Scholar
  • 27 Travis J, Salvesen GS. Human plasma proteinase inhibitors. Ann Rev Biochem 1983; 52: 655-709
    CrossrefPubMedGoogle Scholar
  • 28 Verstraete M, Bounameaux H, de Cock F, van de Werf F, Collen D. Pharmacokinetics and systemic fibrinolytic effects of recombinant tissue type plasminogen activator in humans. J Pharmacol Exp Ther 1985; 235: 506-512
    PubMedGoogle Scholar