title: Preclinical Pharmacokinetics and First-in-Human Pharmacokinetics, Safety, and Tolerability of Velpatasvir, a Pangenotypic Hepatitis C Virus NS5A Inhibitor, in Healthy Subjects.
abstract: Preclinical characterization of velpatasvir (VEL; GS-5816), an inhibitor of the hepatitis C virus (HCV) NS5A protein, demonstrated that it has favorablein vitroandin vivoproperties, including potent antiviral activity against hepatitis C virus genotype 1 to 6 replicons, good metabolic stability, low systemic clearance, and adequate bioavailability and physicochemical properties, to warrant clinical evaluation. The phase 1 (first-in-human) study evaluated the safety, tolerability, and pharmacokinetics of VEL in healthy human subjects following administration of single and multiple (n= 7) once-daily ascending doses and of VEL in the presence and absence of food. Following administration of single and multiple doses, VEL was safe and well tolerated when administered at up to 450 mg and when administered with food. The pharmacokinetic behavior of VEL observed in humans was generally in agreement with that seen during preclinical characterization. Following administration of multiple doses, VEL trough concentrations were significantly greater than the protein-adjusted half-maximal (50%) effective concentration of VEL against HCV genotype 1 to 6 replicons at all evaluated doses greater than 5 mg. The pharmacokinetics of VEL were not significantly affected by administration with food. Collectively, the results of this study support the further clinical investigation of VEL administered once daily as part of a regimen with other pangenotypic direct-acting antivirals for the treatment of HCV infection.
authors.affiliation: Clinical Pharmacology, Gilead Sciences, Inc., Foster City, California, USA erik.mogalian@gilead.com.
authors.forename: Erik
authors.initials: E
authors.lastname: Mogalian
authors.affiliation: Clinical Pharmacology, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Polina
authors.initials: P
authors.lastname: German
authors.affiliation: Clinical Pharmacology, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kearney
authors.affiliation: Drug Metabolism and Pharmacokinetics, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Cheng Yong
authors.initials: CY
authors.lastname: Yang
authors.affiliation: Clinical Research, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Diana
authors.initials: D
authors.lastname: Brainard
authors.affiliation: Medicinal Chemistry, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: John
authors.initials: J
authors.lastname: Link
authors.affiliation: Clinical Research, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: John
authors.initials: J
authors.lastname: McNally
authors.affiliation: Biostatistics, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: LingLing
authors.initials: L
authors.lastname: Han
authors.affiliation: Bioanalytics, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: John
authors.initials: J
authors.lastname: Ling
authors.affiliation: Clinical Pharmacology, Gilead Sciences, Inc., Foster City, California, USA.
authors.forename: Anita
authors.initials: A
authors.lastname: Mathias
mesh_terms: D000328:Adult; D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002219:Carbamates / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004285:Dogs; D005260:Female; D064368:Healthy Volunteers; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy* / Q000821:virology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D006801:Humans; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008875:Middle Aged; D051381:Rats; D017207:Rats, Sprague-Dawley; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D014779:Virus Replication / Q000187:drug effects; D055815:Young Adult; D012324:RNA-Dependent RNA Polymerase; D001562:Benzimidazoles; D001578:Benzopyrans
chemical_list: D000998:Antiviral Agents; D002219:Carbamates; D006576:Heterocyclic Compounds, 4 or More Rings; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C000604171:velpatasvir; D001562:Benzimidazoles; D001578:Benzopyrans
keywords: HCV NS5A inhibitor; clinical trials; pharmacokinetics; safety; velpatasvir