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
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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. / Larrey, Dominique; Lohse, Ansgar W; Trepo, Christian; Bronowicki, Jean-Pierre; Arastéh, Keikawus; Bourlière, Marc; Calleja, Jose Luis; Stern, Jerry O; Nehmiz, Gerhard; Abdallah, Nasri; Berger, Kristi L; Marquis, Martin; Steffgen, Jürgen; Kukolj, George; BI 207127 Study Group.
In: ANTIMICROB AGENTS CH, Vol. 57, No. 10, 01.10.2013, p. 4727-35.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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T1 - 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
AU - Larrey, Dominique
AU - Lohse, Ansgar W
AU - Trepo, Christian
AU - Bronowicki, Jean-Pierre
AU - Arastéh, Keikawus
AU - Bourlière, Marc
AU - Calleja, Jose Luis
AU - Stern, Jerry O
AU - Nehmiz, Gerhard
AU - Abdallah, Nasri
AU - Berger, Kristi L
AU - Marquis, Martin
AU - Steffgen, Jürgen
AU - Kukolj, George
AU - BI 207127 Study Group
PY - 2013/10/1
Y1 - 2013/10/1
N2 - 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.
AB - 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.
KW - Administration, Oral
KW - Adolescent
KW - Adult
KW - Aged
KW - Antiviral Agents
KW - DNA-Directed RNA Polymerases
KW - Double-Blind Method
KW - Female
KW - Hepacivirus
KW - Hepatitis C, Chronic
KW - Humans
KW - Male
KW - Middle Aged
KW - Young Adult
U2 - 10.1128/AAC.00565-13
DO - 10.1128/AAC.00565-13
M3 - SCORING: Journal article
C2 - 23856779
VL - 57
SP - 4727
EP - 4735
JO - ANTIMICROB AGENTS CH
JF - ANTIMICROB AGENTS CH
SN - 0066-4804
IS - 10
ER -