Clinical Pharmacology of Intravenously Administered Recombinant Desulfatohirudin (CGP 39393) in Healthy Volunteers

Ga, Marbet; Verstraete, Marc; Kienast, J.; Gräf, Peter; Hoet, Bernard; Da, Tsakiris; Silling-Engelhardt, G; Close, Philippe

doi:10.1097/00005344-199309000-00004

Cited by 63 publications

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“…The pharmacokinetic data for IK-HIR02 correspond well with the data ob tained in other clinical trials [11,[13][14][15], IK-HIR02 is secreted by E. coli into the fermen tation broth and therefore leads to results very similar to r-hirudins of other producers.…”

Section: Discussionsupporting

confidence: 83%

“…After repeat injections of 0.3 mg/kg s.c. of IK-HIR02, bleeding time was not significantly changed. Measurement of the bleeding time in several human studies on r-hirudin showed variable results [13][14][15]17], Hoet et al [17] observed an increase in 5 and no change in another 5 volunteers. In two of these trials, a mild prolongation in bleeding time was well correlated with moderately high hirudin plasma levels.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

A Recombinant Hirudin (IK-HIR02) in Healthy Volunteers

Schenk¹,

Glusa²,

Radziwon

et al. 1996

Pathophysiol Haemos Thromb

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The pharmacodynamic effects of different intravenous and subcutaneous doses of a recombinant hirudin (r-hirudin; IK-HIR02) on clotting parameters and bleeding time were investigated in 24 healthy volunteers in a bicenter study. Single intravenous bolus injections of 0.1, 0.2 and 0.3 mg/ kg IK-HIR02 caused a prolongation of thrombin time (TT) and aPTT in a dose-dependent manner and led to an increase in hirudin plasma levels > 6 micrograms/ml. The plasma half-life of IK-HIR02 was calculated as 1.3 h. A continuous infusion of 0.03 mg/kg/h of IK-HIR02 for 4 h significantly prolonged TT and aPTT. At the end of the hirudin infusion, a mean plasma level of 0.19 +/- 0.13 microgram/ml was measured. Single subcutaneous doses of 0.1, 0.25 and 0.5 mg/kg markedly prolonged the coagulation tests. The highest increase in hirudin plasma levels was found 2 h after injection. At this time the aPTT was doubled after 0.5 mg/kg. After repeat subcutaneous injections of 0.3 mg/kg b.i.d., aPTT was doubled, and TT increased to about 200 s, 2 h after the injections. At this time the mean plasma level was 0.5-0.6 microgram/ml. There was no cumulative effect after multiple injections. Bleeding time was not changed after the 4-hour intravenous infusion and after repeat subcutaneous injections of 0.3 mg/kg IK-HIR02. Bleeding time was moderately but significantly prolonged after the highest single intravenous and subcutaneous hirudin doses tested. Other than very minor local bleeding in some volunteers, IK-HIR02 was well tolerated. Biochemical blood and urine parameters did not change. In conclusion, r-hirudin (IK-HIR02) obtained by a new technique was well tolerated in healthy volunteers after single intravenous and subcutaneous injections, after repeat subcutaneous doses and during continuous intravenous infusion. Measurement of aPTT and anti-IIa activity, using a chromogenic substrate test, can be used to monitor hirudin effects if doses similar to those tested here are administered.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 99%

A Recombinant Hirudin (IK-HIR02) in Healthy Volunteers

Schenk¹,

Glusa²,

Radziwon

et al. 1996

Pathophysiol Haemos Thromb

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“…[71][72][73][74][75][76] The usefulness of the activated partial-thromboplastin time seems limited by its poor linearity and reproducibility, especially when heparin or a vitamin K antagonist is coadministered. [71][72][73][77][78][79] The ecarin clotting time better reflects the actual plasma concentration of DTIs, but this test is not widely available. [74][75][76][77][80][81][82] heparin-induced thrombocytopenia remaining issues The new england journal of medicine…”

Section: Monitoring Activitymentioning

confidence: 99%

Direct Thrombin Inhibitors

2005

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irect thrombin inhibitors (dti s ) are a new class of anticoagulants that bind directly to thrombin and block its interaction with its substrates. Some DTIs -such as recombinant hirudins, bivalirudin, and ximelagatran, either alone or in combination with melagatran -have undergone extensive evaluation in phase 3 trials for the prevention and treatment of arterial and venous thrombosis. The evidence concerning the clinical applicability of other DTIs, such as argatroban and dabigatran, is limited to phase 2 studies. Four parenteral DTIs have been approved by the Food and Drug Administration (FDA) in North America: hirudin and argatroban for the treatment of heparin-induced thrombocytopenia, bivalirudin as an alternative to heparin in percutaneous coronary intervention, and desirudin as prophylaxis against venous thromboembolism in hip replacement. This review discusses FDA-approved DTIs as well as those under evaluation in phase 2 or 3 clinical trials. coagulation cascade and generation of thrombinAfter injury to a vessel wall, tissue factor is exposed on the surface of the damaged endothelium. The interaction of tissue factor with plasma factor VII activates the coagulation cascade, producing thrombin by stepwise activation of a series of proenzymes ( Fig. 1). Thrombin is central in the clotting process: it converts soluble fibrinogen to fibrin; activates factors V, VIII, and XI, which generates more thrombin; and stimulates platelets. Furthermore, by activating factor XIII, thrombin favors the formation of cross-linked bonds among the fibrin molecules, stabilizing the clot. The coagulation cascade is regulated by natural anticoagulants, such as tissue factor pathway inhibitor, the protein C and protein S system, and antithrombin, all of which help to restrict the formation of the hemostatic plug to the site of injury. differences from heparinsThrombin-inhibiting drugs can block the action of thrombin by binding to three domains: the active site or catalytic site and two exosites (Fig. 2). Located next to the active site, exosite 1 acts as a dock for substrates such as fibrin, thereby orienting the appropriate peptide bonds in the active site. Exosite 2 serves as the heparin-binding domain. 1 Thrombin is inhibited indirectly by low-molecular-weight heparins, because these drugs strongly catalyze the function of antithrombin. A heparin-thrombin-antithrombin complex is formed in which heparin binds simultaneously to exosite 2 in thrombin and to antithrombin. Furthermore, heparin can act as a bridge between thrombin and fibrin by binding both to fibrin and exosite 2 (Fig. 2). Because both thrombin exosites are occupied within this fibrin-heparin-thrombin complex, the enzymatic activity of thrombin is relatively protected from inactivation by the heparin-antithrombin complex. 2-4 Thus, heparins have a reduced capacity for the inhibition of fibrin-bound thrombin, which ap- pears to be detrimental, because active thrombin further triggers thrombus growth.Since DTIs act independently of antithrombin, they can inhibit t...

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“…After continuous infusion of 0.1 mg • kg -1 -h -1 CGP 39393 the peak effect on APTT was observed after 2 to 3 h, resulting in a 2-to 3-fold prolongation of the APTT. After termination of the infusion, APTT-values returned to baseline no later than after 18 to 24 h (Marbet et al 1993, Zoldhelyi et al 1993.…”

mentioning

confidence: 91%

“…Recent and ongoing clinical trials have proved the antithrombotic effects and tolerability of various hirudins in the treatment of venous thromboembolism (Eriksson et al 1994;Parent et a1.1993), the prevention of acute occlusion after PTCA (van den Bos et al 1993) and reocclusion after myocardial infarction (Cannon et al 1993;Neuhaus et al 1993). Prothrombin time, and the thrombin and activated partial thromboplastin (APTT) times are increased after administration of hirudin, whereas a prolongation of bleeding time occured inconsistently and only after high doses (M/irki and Wallis 1990, Marbet et al 1993). APTT appeared to be the most suitable and reliable pharmacodynamic parameter to be measured.…”

mentioning

confidence: 99%

Influence of piroxicam coadministration on pharmacodynamic parameters and the plasma concentration/effect relationship of recombinant hirudin (CGP 39393)

Thürmann

Harder

1995

Eur J Clin Pharmacol

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Recombinant hirudins are currently under investigation for use in myocardial infarction and unstable angina. In this study the influence of piroxicam on the pharmacodynamics and pharmacokinetics of a recombinant hirudin preparation (CGP 39393) administered intravenously was determined. Twelve healthy, male volunteers received piroxicam 10 mg and matching placebo once daily for 12 days according to a double-blind, randomised cross-over design. On the 12th day, the dose of piroxicam was followed by a 6-hour infusion of hirudin 0.1 mg.kg-1.h-1. Plasma concentrations and urinary excretion of hirudin and repeated measurements of the activated partial thromboplastin time (APTT), bleeding time and platelet adhesion index were assessed up to 24 h after the start of the infusion. The maximum APTT was 83 s (placebo) and 84 s (piroxicam), 3 to 4 h after the start of the infusion, and was comparable on both study days. The AUD0-24 (APTT) came to 913 s.h.kg-1 under placebo and it was slightly increased to 1,017 s.h.kg-1 after piroxicam; the 95%- confidence interval according to MOSES ranged from 0.97 to 1.24, and the point estimator was 1.10. Bleeding time was significantly prolonged from 290 s under placebo to 345 s under piroxicam before the start of the infusion of hirudin. No further prolongation was found during or after the infusion. No change was observed in the platelet adhesion index. Responsiveness parameters according to a sigmoidal Emax-model were obtained from the hirudin-plasma concentration/effect (i.e. APTT-prolongation)-curves after placebo and piroxicam.(ABSTRACT TRUNCATED AT 250 WORDS)

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Clinical Pharmacology of Intravenously Administered Recombinant Desulfatohirudin (CGP 39393) in Healthy Volunteers

Cited by 63 publications

References 0 publications

A Recombinant Hirudin (IK-HIR02) in Healthy Volunteers

A Recombinant Hirudin (IK-HIR02) in Healthy Volunteers

Direct Thrombin Inhibitors

Influence of piroxicam coadministration on pharmacodynamic parameters and the plasma concentration/effect relationship of recombinant hirudin (CGP 39393)

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