Ultra-rapid cardiotoxicity of the hepatitis C virus protease inhibitor BILN 2061 in the urokinase-type plasminogen activator mouse.
OBJECTIVE
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 nontransgenic 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.
Vanwolleghem
Thomas
T
Center for Vaccinology, Ghent University and Hospital, Gent, Belgium.
Meuleman
Philip
P
Libbrecht
Louis
L
Roskams
Tania
T
De Vos
Rita
R
Leroux-Roels
Geert
G
D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D002219:Carbamates / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006331:Heart Diseases / Q000139:chemically induced* / Q000473:pathology; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology; D006526:Hepatitis C / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008099:Liver / Q000378:metabolism; D016031:Liver Transplantation; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000648:ultrastructure; D008933:Mitochondrial Swelling / Q000187:drug effects; D023421:Models, Animal; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000648:ultrastructure; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D011804:Quinolines / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D013997:Time Factors; D014183:Transplantation, Heterologous; D014568:Urokinase-Type Plasminogen Activator / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000998:Antiviral Agents; D002219:Carbamates; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles; D014568:Urokinase-Type Plasminogen Activator; D017361:Viral Nonstructural Proteins; C479555:BILN 2061; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases