title: Antiviral activity, safety, and pharmacokinetics of danoprevir/ritonavir plus PEG-IFN α-2a/RBV in hepatitis C patients.
abstract: OBJECTIVE
  Danoprevir (RG7227; ITMN-191) is a potent inhibitor of the HCV NS3/4A serine protease. The aims of this double-blind, placebo-controlled, multiple-ascending dose phase Ib study were to evaluate safety, tolerability, antiviral activity, resistance, and pharmacokinetics of once- and twice-daily danoprevir in the presence of low-dose ritonavir (danoprevir/r) and in combination with peginterferon alfa-2a (40KD)/ribavirin in treatment-naive HCV genotype 1 patients.
  
  
  METHODS
  Thirty eligible patients were enrolled into three cohorts and treated with danoprevir/r or placebo/r all in combination with peginterferon alfa-2a (40KD)/ribavirin for 15 days. Cohort 1 received danoprevir/r at 100/100mg twice daily; Cohort 2 200/100mg once daily; and Cohort 3 200/100mg twice daily.
  
  
  RESULTS
  The median reductions in HCV RNA from baseline after 14 days of treatment (day 15) were -5.1, -4.8, and -4.6 log(10)IU/ml in Cohorts 1, 2, and 3, respectively, and -2.7 log(10) in placebo/r and peginterferon alfa-2a (40KD)/ribavirin recipients. Viral breakthrough was not observed in any patient. On day 15, HCV RNA was undetectable (<15IU/ml) in 6/9 (67%), 4/8 (50%), and 8/8 (100%) patients in Cohorts 1, 2, and 3, respectively. When co-administered with low dose ritonavir, danoprevir concentrations reached a steady state between 6 to 10 days of dosing. Danoprevir exposures increased more than dose proportionally between 100/100mg and 200/100mg. Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin was well-tolerated with no safety-related discontinuations.
  
  
  CONCLUSIONS
  Danoprevir/r plus peginterferon alfa-2a (40KD)/ribavirin provides profound and robust reductions in serum HCV RNA, at substantially lower systemic exposures compared to those observed with higher doses of danoprevir in the absence of ritonavir. These results support further studies of danoprevir/r.
authors.affiliation: Auckland Clinical Studies, New Zealand.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Gane
authors.forename: Regine
authors.initials: R
authors.lastname: Rouzier
authors.forename: Catherine
authors.initials: C
authors.lastname: Stedman
authors.forename: Alicja
authors.initials: A
authors.lastname: Wiercinska-Drapalo
authors.forename: Andrzej
authors.initials: A
authors.lastname: Horban
authors.forename: Linda
authors.initials: L
authors.lastname: Chang
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Pratibha
authors.initials: P
authors.lastname: Sampeur
authors.forename: Isabel
authors.initials: I
authors.lastname: Nájera
authors.forename: Patrick
authors.initials: P
authors.lastname: Smith
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Shulman
authors.forename: Jonathan Q
authors.initials: JQ
authors.lastname: Tran
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D003521:Cyclopropanes; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000009:adverse effects / Q000627:therapeutic use*; D054833:Isoindoles; D007769:Lactams / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047029:Lactams, Macrocyclic; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000009:adverse effects / Q000627:therapeutic use*; D011392:Proline / Q000031:analogs & derivatives; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins / Q000009:adverse effects / Q000627:therapeutic use; D012254:Ribavirin / Q000009:adverse effects / Q000627:therapeutic use*; D019438:Ritonavir / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D013997:Time Factors
chemical_list: D000998:Antiviral Agents; D003521:Cyclopropanes; D016898:Interferon-alpha; D054833:Isoindoles; D007769:Lactams; D047029:Lactams, Macrocyclic; D012367:RNA, Viral; D011994:Recombinant Proteins; D013449:Sulfonamides; D011092:Polyethylene Glycols; D012254:Ribavirin; C553752:danoprevir; D011392:Proline; D019438:Ritonavir; C100416:peginterferon alfa-2a