title: A randomized, double blind, dose escalation, first time in human study to assess the safety, tolerability, pharmacokinetics, and antiviral activity of single doses of GSK2485852 in chronically infected hepatitis C subjects.
abstract: This first-time-in-human, randomized, double-blind, placebo-controlled, dose-escalation study assessed the safety, tolerability, pharmacokinetics, and antiviral activity of GSK2485852, a hepatitis C virus (HCV) NS5B inhibitor, in 27 chronically infected HCV genotype-1 subjects. Subjects received GSK2485852 70, 420, and 70 mg with a moderate fat/caloric meal. Safety, pharmacokinetics, antiviral activity, HCV genotype/phenotype, and interleukin 28B genotype were evaluated. A statistically significant reduction in HCV ribonucleic acid (RNA) was observed after a single dose of 420 mg GSK2485852 (-1.33 log10  IU/mL) compared with placebo (-0.09 log10  IU/mL) at 24 hours post-dose. Subjects receiving 70 mg GSK2485852 were exposed to concentrations above the protein-adjusted 90% effective concentration for a short time; none experienced a significant decline in HCV RNA (-0.47 log10  copies/mL). GSK2485852 was readily absorbed; however, the observed geometric mean maximum plasma concentration (Cmax ) and area under the curve (AUC) values were significantly lower than expected due to a higher-than-predicted-oral clearance. Co-administration with food reduced the AUC and Cmax of GSK2485852 by 40% and 70%, respectively. Two metabolites were detected in human blood with one having approximately 50% higher concentrations than those of the parent. GSK2485852 was well-tolerated and exhibited antiviral activity after a single 420 mg dose in HCV subjects.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Wilfret
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Jill
authors.initials: J
authors.lastname: Walker
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Voitenleitner
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Sharon
authors.initials: S
authors.lastname: Baptiste-Brown
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lovern
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Kim
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Adkison
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Brad
authors.initials: B
authors.lastname: Shotwell
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Mathis
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Moss
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lee
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Lou
authors.initials: L
authors.lastname: Yu
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Jianjun
authors.initials: J
authors.lastname: Gan
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Spaltenstein
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D001897:Boronic Acids / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D004311:Double-Blind Method; D005260:Female; D018565:Food-Drug Interactions; D005838:Genotype; D016174:Hepacivirus / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D007372:Interferons; D007378:Interleukins / Q000235:genetics; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011480:Protease Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D012367:RNA, Viral / Q000097:blood; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014481:United States; D019562:Viral Load; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055815:Young Adult; D000095022:Interferon Lambda; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D001897:Boronic Acids; D007372:Interferons; D007378:Interleukins; D011480:Protease Inhibitors; D012367:RNA, Viral; D013449:Sulfonamides; D017361:Viral Nonstructural Proteins; C588298:GSK2485852; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: GSK2485852; NS5B inhibitor; Phase 1; first-time-in-human; hepatitis C