Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse

Vanwolleghem, Thomas; Meuleman, Philip; Libbrecht, Louis; Roskams, Tania; De Vos, Rita; Leroux-Roels, Geert

doi:10.1053/J.GASTRO.2007.07.007

Title

Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse

Author

Vanwolleghem, Thomas

Meuleman, Philip

Libbrecht, Louis

Roskams, Tania

De Vos, Rita

Leroux-Roels, Geert

Abstract

Background & Aims: Because current therapies for chronic hepatitis C virus (HCV) infections are suboptimal and associated with severe side effects, novel treatment options are needed. A small animal model has recently been developed to study HCV infections. To examine the usefulness of this human liver-urokinase-type plasminogen activator (uPA)(+/+) severe combined immune deficient (SCID) mouse for the development of HCV-targeted drugs, we evaluated the antiviral efficacy and safety of an HCV NS3-protease inhibitor, BILN 2061. Methods: BILN 2061 was orally administered at clinical range doses for 4 days to SCID mice that differed in the presence of HCV infection, human hepatocyte grafts, and uPA zygosity. Treatment outcome was evaluated clinically, virologically, and morphologically. Using standard high-performance liquid chromatography- ultraviolet (HPLC-UV) methods and mass spectrometry, single-dose pharmacokinetics and multiple-dose drug exposures were analyzed. The 13 C-aminopyrine breath test was applied to compare in vivo liver function. Results: A 4-day treatment with BILN 2061 of HCV genotype-1b infected chimeric animals reduced the viral load by > 100-fold, but concomitant clinical and ultrastructural signs of cardiotoxicity appeared. BILN 2061 administration to uPA-transgenic mice induced mitochondrial swelling with aberrant cristae in cardiomyocytes, but not in skeletal muscle. Because both drug accumulation and liver function were identical in affected uPA-transgenic and non-transgenic SCID mice without cardiac involvement, the urokinase plasminogen activator transgene itself appears to be implicated. Conclusions: The human liver-uPA(+/+)SCID mouse is an interesting small animal model to evaluate the preclinical safety and efficacy of new antiviral compounds against HCV. The uPA-transgene increases the susceptibility of mice to BILN 2061-induced cardiotoxicity.

Language

English

Source (journal)

Gastroenterology. - Baltimore, Md

Publication

Baltimore, Md : 2007

ISSN

0016-5085

DOI

10.1053/J.GASTRO.2007.07.007

Volume/pages

133 :4 (2007) , p. 1144-1155