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. Issue 6 (20th October 2014)

• Record Type: Journal Article
• 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
• Is Part Of: Clinical pharmacology in drug development. Volume 3:Issue 6(2014:Nov./Dec.)
• Page Start: 439
• Page End: 448
• Publication Date: 2014-10-20
• Subjects: Drugs -- Testing -- Periodicals; Drug development -- Periodicals; Clinical pharmacology -- Periodicals; 615.580724
• DOI: 10.1002/cpdd.142
• Languages: English
• ISSNs: 2160-7648

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Abstract</title> <sec id="cpdd142-sec-0001" sec-type="section"> <p>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 log<sub>10</sub> IU/mL) compared with placebo (−0.09 log<sub>10</sub> 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 log<sub>10</sub> copies/mL). GSK2485852 was readily absorbed; however, the observed geometric mean maximum plasma concentration (C<sub>max</sub>) 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 C<sub>max</sub> 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.</p> </sec> </abstract>