title: Rapid decline of viral RNA in chronic hepatitis C patients treated once daily with IDX320: a novel macrocyclic HCV protease inhibitor.
abstract: BACKGROUND
  The addition of direct-acting antivirals to pegylated interferon-α plus ribavirin for the treatment of chronic HCV infection can result in an increased sustained viral response rate and may permit reduction in treatment duration. IDX320 is a potent non-covalent macrocyclic inhibitor of the HCV NS3/4A protease.
  
  
  METHODS
  This was a randomized double-blind placebo-controlled single- and multiple-dose study to assess the safety, tolerability, antiviral activity and pharmacokinetics of IDX320 in healthy volunteers (HV) and patients with chronic HCV genotype 1 infection. HV (n=48) received single or multiple ascending doses of IDX320. Two HCV-infected patients received a single dose of 200 mg IDX320. Dosages for other HCV-infected patients were as follows: placebo, 50, 100, 200 or 400 mg of IDX320 orally once daily for 3 days (n=30) or placebo/200 mg of IDX320 twice-daily for 3 days (n=8).
  
  
  RESULTS
  In total, 48 HV and 40 HCV-infected patients were enrolled and all completed the study. There were no serious adverse events. The majority of adverse events were of mild or moderate intensity. Pharmacokinetics supported a once-daily dosing regimen. A rapid decline in plasma HCV RNA was observed in all patients. In the multiple-dose study, mean HCV RNA reductions were 2.6, 3.1, 3.1, 3.3 and 3.8 log(10) IU/ml after 3 days in the IDX320 50, 100, 200, 400 mg once-daily and 200 mg twice-daily treatment groups, respectively. This compared to a mean HCV RNA reduction of 0.04 log(10) in the placebo group.
  
  
  CONCLUSIONS
  Once-daily IDX320 dosing demonstrated potent dose-dependent antiviral activity in treatment-naive HCV genotype-1-infected patients.
authors.affiliation: Academic Medical Center, Amsterdam, the Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: de Bruijne
authors.forename: Andre
authors.initials: A
authors.lastname: van Vliet
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Weegink
authors.forename: Włodzimierz
authors.initials: W
authors.lastname: Mazur
authors.forename: Alicja
authors.initials: A
authors.lastname: Wiercinska-Drapało
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Simon
authors.forename: Grażyna
authors.initials: G
authors.lastname: Cholewińska-Szymańska
authors.forename: Judit
authors.initials: J
authors.lastname: Kapocsi
authors.forename: István
authors.initials: I
authors.lastname: Várkonyi
authors.forename: Xiao-Jian
authors.initials: XJ
authors.lastname: Zhou
authors.forename: Marie-Francoise
authors.initials: MF
authors.lastname: Temam
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Molles
authors.forename: Jie
authors.initials: J
authors.lastname: Chen
authors.forename: Keith
authors.initials: K
authors.lastname: Pietropaolo
authors.forename: Joseph F
authors.initials: JF
authors.lastname: McCarville
authors.forename: John Z
authors.initials: JZ
authors.lastname: Sullivan-Bólyai
authors.forename: Douglas
authors.initials: D
authors.lastname: Mayers
authors.forename: Hendrik
authors.initials: H
authors.lastname: Reesink
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005838:Genotype; D006207:Half-Life; D016174:Hepacivirus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D047028:Macrocyclic Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D011480:Protease Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012367:RNA, Viral / Q000097:blood*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; C574703:IDX320; D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D012367:RNA, Viral