Subscribe to RSS
DOI: 10.1055/s-0038-1656028
Pharmacokinetics of Recombinant Hirudin in Hemodialyzed End-stage Renal Failure Patients
Publication History
Received 05 March 1996
Accepted after revision 19 December 1996
Publication Date:
11 July 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199704/lookinside/thumbnails/10-1055-s-0038-1656028-1.jpg)
Summary
Recently, hirudin was used for the first time as an anticoagulant during hemodialysis in men. Pharmacokinetic data of this compound in end-stage renal failure are however not available. In this study, the pharmacokinetics of recombinant hirudin (HBW 023) was evaluated in hemodialysis-treated end-stage renal failure patients. HBW 023 was administered as a bolus at the start of a single dialysis (0.02 to 0.08 mg/kg) in 20 patients, and plasma hirudin levels were followed during this and the 5 following dialyses, without additional hirudin administration. The initial dialysis (HDj) was performed with a low flux polysulfone dialyzer; the following dialyses (up to HD6) with a high flux polysulfone dialyzer and regular heparin. Hirudin levels averaged 504.0 ± 214.0 and 527.7 ± 217.1 ng/ml in the middle and at the end of HDj, and then gradually decreased to 15.2 ± 15.2 ng/ml at the end of HD6. Pharmacokinetic data were compared to those obtained in healthy controls (n = 5), receiving the same dose, and reaching the same peak hirudin level. Hirudin half-life was >30 times longer in hemodialysis patients (51.8 ± 15.6 vs. 1.7 ± 1.5 h, p <0.001), whereas area under the curve was >60 times higher (34,669 ± 14,898 vs. 545 ± 205 ng/ml X h, p <0.001). Distribution volume was lower in hemodialysis patients (11.0 ± 3.1 vs. 14.1 ± 2.0 1, p <0.05). Hirudin disappearance rate was the same during high flux polysulfone dialysis as during interdialytic periods. Hirudin removal was markedly higher in those patients still maintaining some residual renal function and parameters of hirudin removal were significantly correlated to residual creatinine clearance. It is concluded that hirudin removal from the body is markedly depressed in hemodialyzed end-stage renal failure patients and that even minor residual renal function may increase this removal rate.
-
References
- 1 Rydel TJ, Ravichandran KG, Tulinsky A, Bode W, Huber R, Roitsch C, Fenton JW. The structure of a complex of recombinant hirudin and human a-thrombin. Science 1990; 249: 277-280
- 2 Markwardt F. Hirudin and derivatives as anticoagulant agents. Thromb Haemost 1991; 66: 141-152
- 3 Anonymous. Editorial. Hirudins: return of the leach?. Lancet 1992; 340: 579-580
- 4 Hirsh J. Heparin. N Engl J Med 1991; 324: 1565-1574
- 5 Freedman MD. Pharmacodynamics, clinical indications, and adverse effects of heparin. J Clin Pharmacol 1992; 32: 584-596
- 6 Hirsh J, Dalen JE, Deykin D, Poller L. Heparin: Mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chestl 1992; 102: S337-S351
- 7 Hull RD, Raskob GE, Pineo GF, Green D, Trowbridge AA, Elliott CG, Lemer RG, Hall J, Sparling T, Brettell HR, Norton J, Carter CJ, George R, Merli G, Ward J, Mayo W, Rosenblum D, Brant R. Subcutaneous lowmolecular weight heparin compared with continuous intravenous heparin in the treatment of proximal-vein thrombosis. N Engl J Med 1992; 326: 975-982
- 8 Neuhaus KL, vEssen R, Tebbe U, Vogt A, Michels HR, Appel KF, Jessel A, Zeymer U. Hirudin and thrombolysis with front-loaded alteplase in acute myocardial infarction. Results of a pilot study. J Am Coll Cardiol 1993; 21 (Suppl. 02) 418A (abstract).
- 9 Cannon CP, McCabe CH, Henry DT, Rogers WJ, Schweiger M, Gibson RS, Anderson JL, Williams DO, Braunwald E. Hirudin reduces reocclusion compared to heparin following thrombolysis in acute myocardial infarction: Results of the TIMI5 study. J Am Coll Cardiol 1993; 21 (Suppl. 02) 136A (abstract).
- 10 Sharaf BL, Miele N, Ferreira P, McKendall GR, Williams DO. Culprit lesion changes in acute myocardial infarction: a TIMI 5 comparison of patients treated with t-PA and either heparin or hirudin. J Am Coll Cardiol 1993; 21 (Suppl. 02) 419A (abstract).
- 11 Agnelli G, Renga C, Weitz JI, Nenci GG, Hirsh J. Sustained antithrombotic activity of hirudin after its plasma clearance: comparison with heparin. Blood 1992; 80: 960-965
- 12 Bucha E, Markwardt F, Nowak G. Hirudin in haemodialysis. Thromb Res 1990; 60: 445-455
- 13 Nowak G, Bucha E, Gööck Th, Thieler H, Markwardt F. Pharmacology of r-hirudin in renal impairment. Thromb Res 1992; 66: 707-715
- 14 Vanholder RC, Camez AA, Veys NM, Soria J, Mirshahi M, Soria C, Ringoir S. Recombinant hirudin: a specific thrombin inhibiting anticoagulant for hemodialysis. Kidney Int 1994; 45: 1754-1759
- 15 Griessbach U, Stürzebecher J, Markwardt F. Assay of hirudin in plasma using a chromogenic thrombin substrate. Thromb Res 1985; 37: 347-350
- 16 Groetsch H, Berscheid G, Hropot M, Ben YoussefR. Interference of heparin and analogues with hirudin in the chromogenic thrombin substrate assay. Thromb Res 1991; 64: 285-290
- 17 Meyer BH, Luus HG, Müller FO, Badenhorst PN, Röthig HJ. The pharmacology of recombinant hirudin, a new anticoagulant. S Afr Med J 1990; 78: 268-270
- 18 Zoldhelyi P, Webster MWI, Fuster V, Grill DE, Gaspar D, Edwards SJ, Cabot CF, Chesebro JH. Recombinant hirudin in patients with chronic, stable coronary artery disease. Safety, half-life, and effect on coagulation parameters. Circulation 1993; 88: 2015-2022
- 19 Grötsch H, Hropot M. Degradation of rDNA hirudin and a-human thrombin hirudin complex in liver and kidney homogenates from rat. Thromb Res 1991; 64: 763-767
- 20 Vanholder R, Hsu C, Ringoir S. Biochemical definition of the uremic syndrome and possible therapeutic implications. Artif Organs 1993; 17: 234-239
- 21 Hsu CH, Patel SR, Vanholder R. Mechanism of decreased intestinal calcitriol receptor concentration in renal failure. Am J Physiol 1993; 264: F662-F669
- 22 Hirsh J, Levine MN. Low molecular weight heparin. Blood 1992; 79: 01-17
- 23 Vitoux JF, Mathieu JF, Roncato M, Fiessinger JN, Aiach M. Heparin associated thrombocytopenia: treatment with low molecular weight heparin. Thromb Haemost 1986; 55: 37-39
- 24 Horellou MH, Conard J, Lecrubier C, Samama M, Roque-D’Orbcastel O, de FenoylO, Di MariaG, Bemadou A. Persistent heparin induced thrombocytopenia despite therapy with low molecular weight heparin. Thromb Haemost 1984; 51: 134 (letter).
- 25 Vanholder R, De SmetR, Hsu C, Vogeleere P, Ringoir S. Uremic toxicity: the middle molecule hypothesis revisited. Sem Nephrol 1994; 14: 205-218