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Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis

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Abstract

Purpose

To assess the effect of tezosentan, a parenteral dual ET receptor antagonist, on splanchnic and systemic hemodynamics in patients with cirrhosis. In addition, the safety, pharmacokinetics, and pharmacodynamics of tezosentan were evaluated.

Methods

The population consisted of patients with cirrhosis with clinically significant portal hypertension. This was a randomized, double-blind, multicenter study. The patients were randomized 3:1 to tezosentan (3 mg/h for 2–3 h) or placebo. HVPG, hepatic blood flow (HBF, ICG method), and systemic arterial pressures were measured before and after tezosentan administration. Plasma concentrations of tezosentan and ET-1 were determined peripherally and in the hepatic vein.

Results

Eighteen patients received tezosentan and six placebo. Baseline clinical, biochemical, and hemodynamic characteristics were balanced between the two groups. There was no significant treatment effect on HVPG. The extraction ratio (0.31), the plasma clearance of ICG (280 ml/min), and the HBF (1,430 ml/min) did not show any relevant changes during the infusion of tezosentan, and there were no differences between placebo- and tezosentan-treated patients. A linear relationship was observed between the maximum-fold increase in ET-1 concentration and the steady-state tezosentan plasma concentration (r = 0.82). There was a strong correlation (r = 0.88) between plasma clearance of ICG and that of tezosentan (10.2 l/h). Arterial pressure and heart rate did not significantly change in either group.

Conclusion

In patients with cirrhosis, a 2- to 3-h tezosentan infusion was safe and well tolerated but did not change the HVPG. Tezosentan infusion had no influence on the extraction ratio and plasma clearance of ICG and did not change HBF.

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Abbreviations

CL:

Clearance

E:

Extraction ratio

HBF:

Hepatic blood flow

HR:

Heart rate

HVPG:

Hepatic venous pressure gradient

ICG:

Indocyanine green

MAP:

Mean arterial pressure

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Authors and Affiliations

  1. Unité 773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, INSERM, Paris, France

    Didier Lebrec & Richard Moreau

  2. Service d’Hépatologie, Hôpital Beaujon, Clichy, France

    Didier Lebrec & Richard Moreau

  3. Hepatic Hemodynamic Laboratory, Liver Unit Hospital IDIBAP and Ciberehd, Barcelona, Spain

    Jaime Bosch & Juan Carlos Garcia-Pagan

  4. Institute of Hepatology, University College London Medical School, London, UK

    Rajiv Jalan & Rajeshwar P. Mookerjee

  5. Alfred Hospital and Baker Research Institute, Prahran, Victoria, Australia

    Francis J. Dudley

  6. Institute for Digestive Diseases, Clinic for Gastroenterology and Hepatology, Belgrade, Serbia

    Rada Jessic

  7. Clinical Development, Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123, Allschwil, Switzerland

    Eleonora Chiossi, Paul L. M. Van Giersbergen, Andjela Kusic-Pajic & Jasper Dingemanse

Authors
  1. Didier Lebrec
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  2. Jaime Bosch
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  3. Rajiv Jalan
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  6. Richard Moreau
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  8. Rajeshwar P. Mookerjee
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  9. Eleonora Chiossi
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  12. Jasper Dingemanse
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Correspondence to Jasper Dingemanse.

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Lebrec, D., Bosch, J., Jalan, R. et al. Hemodynamics and pharmacokinetics of tezosentan, a dual endothelin receptor antagonist, in patients with cirrhosis. Eur J Clin Pharmacol 68, 533–541 (2012). https://doi.org/10.1007/s00228-011-1157-6

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  • DOI: https://doi.org/10.1007/s00228-011-1157-6

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