title: A twenty-eight-day mechanistic time course study in the rhesus monkey with hepatitis C virus protease inhibitor BILN 2061.
abstract: BILN 2061 is a potent, reversible inhibitor of hepatitis C virus NS3/NS4A serine protease. Early clinical proof of principle with the drug was offset by the results of subsequent safety studies in Rhesus monkeys revealing cardiotoxicity that featured myocardial vacuolation corresponding to mitochondrial swelling. Here we describe an investigation into the nature, onset, and reversibility of the lesion, and an assessment of potentially predictive biomarkers for the change. Rhesus monkeys were orally administered 1,000 mg/kg/day BILN 2061 and either necropsied after one, three, fourteen, or twenty-eight doses or afforded a ten-week recovery period. The results of electrocardiographic and plasma troponin I and T measurements were unaffected by BILN 2061, but cardiac myocytic vacuolation, correlated with mitochondrial swelling, was observed after three or more doses. Echocardiographic traces obtained after twenty-eight consecutive days of dosing revealed two animals with diminished left ventricular cardiac ejection fraction. One animal was immediately necropsied and exhibited marked cardiotoxicity. The other was afforded a ten-week treatment-free period during which the left ventricular ejection fraction returned to normal. All recovery animal hearts were microscopically and ultrastructurally normal. High-dose BILN 2061 cardiotoxicity in Rhesus monkeys appeared early in the treatment regimen and exhibited reversibility. A reliable biomarker has yet to be identified.
authors: Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut 06877-0368, USA. jim.stoltz@boehringer-ingelheim.com
authors: James H
authors: JH
authors: Stoltz
authors: Jerry O
authors: JO
authors: Stern
authors: Qihong
authors: Q
authors: Huang
authors: Randolph W
authors: RW
authors: Seidler
authors: Franklin D
authors: FD
authors: Pack
authors: Brian L
authors: BL
authors: Knight
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology / Q000633:toxicity; D015415:Biomarkers; D002219:Carbamates / Q000494:pharmacology / Q000633:toxicity*; D054715:Cardiotoxins / Q000494:pharmacology / Q000633:toxicity; D004353:Drug Evaluation, Preclinical; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D008253:Macaca mulatta; D047028:Macrocyclic Compounds / Q000494:pharmacology / Q000633:toxicity*; D008297:Male; D008933:Mitochondrial Swelling / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects; D011480:Protease Inhibitors / Q000494:pharmacology / Q000633:toxicity*; D011804:Quinolines / Q000494:pharmacology / Q000633:toxicity*; D057057:Serine Proteases / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology / Q000633:toxicity*; D017361:Viral Nonstructural Proteins
chemical_list: D000998:Antiviral Agents; C479555:BILN 2061; D015415:Biomarkers; D002219:Carbamates; D054715:Cardiotoxins; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011804:Quinolines; D013844:Thiazoles; D017361:Viral Nonstructural Proteins; D057057:Serine Proteases