Use of Multiple Probes to Assess Transporter- and Cytochrome P450-Mediated Drug-Drug Interaction Potential of the Pangenotypic HCV NS5A Inhibitor Velpatasvir

Clin Pharmacokinet. 2016 May;55(5):605-13. doi: 10.1007/s40262-015-0334-7.


Background and objectives: Velpatasvir (VEL; GS-5816) is a potent, pangenotypic hepatitis C virus (HCV), non-structural protein 5A inhibitor in clinical development for the treatment of chronic HCV infection. In vitro studies indicate that VEL may inhibit several drug transporters and be a substrate for enzyme/drug transport systems in vivo. The purpose of this study was to evaluate the potential of VEL as a perpetrator or victim of metabolic- and transporter-based drug-drug interactions using complementary probe drugs.

Methods: This Phase 1 study was a randomized, cross-over, open-label, single- and multiple-dose, five-cohort study. Serial blood samples were collected following oral administration of reference and test treatments. The primary pharmacokinetic parameters of each analyte were compared when administered alone or in combination. The 90% confidence intervals (CI) for the ratio of the geometric least-squares means of the test and reference treatments was calculated for each analyte and parameter of interest.

Results: This study demonstrated that VEL is a weak (P-gp, OATP) to moderate (breast cancer resistance protein) transport inhibitor. As a victim of interactions, VEL is moderately affected by potent inhibitors and to a greater extent, potent inducers of enzyme/drug transporter systems.

Conclusions: The impact of specific transporters and overall contribution of drug transport vs. metabolizing enzymes on the disposition of VEL was characterized through the use of complementary probes, despite the lack of phenotypic specificity, and informs a broad range of drug-drug interaction recommendations.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Antiviral Agents / adverse effects
  • Antiviral Agents / pharmacokinetics*
  • Antiviral Agents / pharmacology
  • Carbamates / adverse effects
  • Carbamates / pharmacokinetics*
  • Carbamates / pharmacology
  • Cross-Over Studies
  • Cytochrome P-450 Enzyme System / metabolism*
  • Drug Interactions
  • Female
  • Hepacivirus
  • Heterocyclic Compounds, 4 or More Rings / adverse effects
  • Heterocyclic Compounds, 4 or More Rings / pharmacokinetics*
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Humans
  • Male
  • Membrane Transport Proteins / metabolism*
  • Middle Aged
  • Young Adult


  • Antiviral Agents
  • Carbamates
  • Heterocyclic Compounds, 4 or More Rings
  • Membrane Transport Proteins
  • Cytochrome P-450 Enzyme System
  • velpatasvir