title: Treatment of chronic hepatitis C patients with the NS3/4A protease inhibitor danoprevir (ITMN-191/RG7227) leads to robust reductions in viral RNA: a phase 1b multiple ascending dose study.
abstract: OBJECTIVE
  Danoprevir is a potent and selective inhibitor of the hepatitis C virus (HCV) NS3/4A serine protease. The present study assessed the safety, pharmacokinetics, and antiviral activity of danoprevir in a randomized, placebo-controlled, 14-day multiple ascending dose study in patients with chronic HCV genotype 1 infection.
  
  
  METHODS
  Four cohorts of treatment-naïve (TN) patients (100 mg q12 h, 100 mg q8 h, 200 mg q12 h, 200 mg q8 h) and one cohort of non-responders (NR) to prior pegylated interferon alfa-ribavirin treatment (300 mg q12 h) were investigated.
  
  
  RESULTS
  Danoprevir was safe and well tolerated; adverse events were generally mild, transient and were not associated with treatment group or dose level. Danoprevir displayed a slightly more than proportional increase in exposure with increasing daily dose and was rapidly eliminated from the plasma compartment. Maximal decreases in HCV RNA were: -3.9 log(10)IU/ml and -3.2 log(10)IU/ml in TN receiving 200 mg q8 h and 200 mg q12 h, respectively. End of treatment viral decline in these two cohorts was within 0.1 log(10)IU/ml of the viral load nadir. HCV RNA reduction in NR was more modest than that observed in upper dose TN cohorts. The overall incidence of viral rebound was low (10/37) and was associated with the R155K substitution in NS3 regardless of the HCV subtype.
  
  
  CONCLUSIONS
  Danoprevir was safe and well tolerated when administered for 14 days in patients with chronic HCV genotype 1 infection. Treatment resulted in sustained, multi-log(10) IU/ml reductions in HCV RNA in upper dose cohorts. These results support further clinical evaluation of danoprevir in patients with chronic HCV.
authors.affiliation: J.W. Goethe Universität, Frankfurt, Germany. nicole.forestier@kgu.de
authors.forename: Nicole
authors.initials: N
authors.lastname: Forestier
authors.forename: Dominique
authors.initials: D
authors.lastname: Larrey
authors.forename: Dominique
authors.initials: D
authors.lastname: Guyader
authors.forename: Patrick
authors.initials: P
authors.lastname: Marcellin
authors.forename: Régine
authors.initials: R
authors.lastname: Rouzier
authors.forename: Alain
authors.initials: A
authors.lastname: Patat
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: Williamson
authors.initials: W
authors.lastname: Bradford
authors.forename: Steven
authors.initials: S
authors.lastname: Porter
authors.forename: Lawrence
authors.initials: L
authors.lastname: Blatt
authors.forename: Scott D
authors.initials: SD
authors.lastname: Seiwert
authors.forename: Stefan
authors.initials: S
authors.lastname: Zeuzem
mesh_terms: D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D003521:Cyclopropanes; D004311:Double-Blind Method; D024882:Drug Resistance, Viral / Q000235:genetics; D005260:Female; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000821:virology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage; D047908:Intracellular Signaling Peptides and Proteins; D054833:Isoindoles; D007769:Lactams / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D047029:Lactams, Macrocyclic; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage; D011392:Proline / Q000031:analogs & derivatives; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D019562:Viral Load / Q000187:drug effects; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D000410:Alanine Transaminase; D000998:Antiviral Agents; D002352:Carrier Proteins; D003521:Cyclopropanes; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D047908:Intracellular Signaling Peptides and Proteins; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D011092:Polyethylene Glycols; D011392:Proline; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C455041:NS4A cofactor peptide, Hepatitis C virus; C553752:danoprevir; C100416:peginterferon alfa-2a