title: Antiviral effect, safety, and pharmacokinetics of five-day oral administration of Deleobuvir (BI 207127), an investigational hepatitis C virus RNA polymerase inhibitor, in patients with chronic hepatitis C.
abstract: Deleobuvir (BI 207127) is an investigational oral nonnucleoside inhibitor of hepatitis C virus (HCV) NS5B RNA polymerase. Antiviral activity, virology, pharmacokinetics, and safety were assessed in HCV genotype 1-infected patients receiving 5 days' deleobuvir monotherapy. In this double-blind phase 1b study, treatment-naive (TN; n = 15) and treatment-experienced (TE; n = 45) patients without cirrhosis received placebo or deleobuvir at 100, 200, 400, 800, or 1,200 mg every 8 h (q8h) for 5 days. Patients with cirrhosis (n = 13) received deleobuvir at 400 or 600 mg q8h for 5 days. Virologic analyses included NS5B genotyping and phenotyping of individual isolates. At day 5, patients without cirrhosis had dose-dependent median HCV RNA reductions of up to 3.8 log10 (with no placebo response); patients with cirrhosis had median HCV RNA reductions of approximately 3.0 log10. Three patients discontinued due to adverse events (AEs). The most common AEs were gastrointestinal, nervous system, and skin/cutaneous tissue disorders. Plasma exposure of deleobuvir was supraproportional at doses ≥ 400 mg q8h and approximately 2-fold higher in patients with cirrhosis than in patients without cirrhosis. No virologic breakthrough was observed. NS5B substitutions associated with deleobuvir resistance in vitro were detected in 9/59 patients; seven encoded P495 substitutions, including P495L, which conferred 120- to 310-fold-decreased sensitivity to deleobuvir. P495 variants did not persist in follow-up without selective drug pressure. Deleobuvir monotherapy was generally well tolerated and demonstrated dose-dependent antiviral activity against HCV genotype 1 over 5 days.
authors.affiliation: Département d'Hépato-Gastroentérologie, Hôpital Saint Eloi, Montpellier, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Larrey
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.forename: Christian
authors.initials: C
authors.lastname: Trepo
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Bronowicki
authors.forename: Keikawus
authors.initials: K
authors.lastname: Arastéh
authors.forename: Marc
authors.initials: M
authors.lastname: Bourlière
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Calleja
authors.forename: Jerry O
authors.initials: JO
authors.lastname: Stern
authors.forename: Gerhard
authors.initials: G
authors.lastname: Nehmiz
authors.forename: Nasri
authors.initials: N
authors.lastname: Abdallah
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Berger
authors.forename: Martin
authors.initials: M
authors.lastname: Marquis
authors.forename: Jürgen
authors.initials: J
authors.lastname: Steffgen
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
mesh_terms: D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors; D004311:Double-Blind Method; D005260:Female; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D012321:DNA-Directed RNA Polymerases