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

• Published in: Clinical pharmacology in drug development 2014-11, Vol.3 (6), p.439-448
• Main Authors: Wilfret, David A., Walker, Jill, Voitenleitner, Christian, Baptiste-Brown, Sharon, Lovern, Mark, Kim, Joseph, Adkison, Kimberly, Shotwell, Brad, Mathis, Amanda, Moss, Lee, Lee, Daniel, Yu, Lou, Gan, Jianjun, Spaltenstein, Andrew
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Antiviral Agents - administration & dosage; Antiviral Agents - adverse effects; Antiviral Agents - pharmacokinetics; Boronic Acids - administration & dosage; Boronic Acids - adverse effects; Boronic Acids - pharmacokinetics; Double-Blind Method; Female; first-time-in-human; Food-Drug Interactions; Genotype; GSK2485852; Hepacivirus - drug effects; Hepacivirus - enzymology; Hepacivirus - genetics; Hepatitis; hepatitis C; Hepatitis C, Chronic - blood; Hepatitis C, Chronic - diagnosis; Hepatitis C, Chronic - drug therapy; Hepatitis C, Chronic - genetics; HIV; Human immunodeficiency virus; Humans; Interferons; Interleukins - genetics; Male; Middle Aged; NS5B inhibitor; Phase 1; Phenotype; Protease Inhibitors - administration & dosage; Protease Inhibitors - adverse effects; Protease Inhibitors - pharmacokinetics; RNA, Viral - blood; Sulfonamides - administration & dosage; Sulfonamides - adverse effects; Sulfonamides - pharmacokinetics; Treatment Outcome; United States; Viral Load; Viral Nonstructural Proteins - antagonists & inhibitors; Viral Nonstructural Proteins - metabolism; Young Adult
• ISSN: 2160-763X; 2160-7648
• DOI: 10.1002/cpdd.142

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.