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

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Abstract

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.

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Acknowledgments

The authors would like to thank the volunteers and staff who participated in the study. The work was previously presented at the 15th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy, May 19–21, 2014, Washington, DC, USA.

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Authors and Affiliations

  1. Gilead Sciences, Inc., 333 Lakeside Dr., Foster City, CA, 94404, USA

    Erik Mogalian, Polina German, Brian P. Kearney, Cheng Yong Yang, Diana Brainard, John McNally, Lisa Moorehead & Anita Mathias

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  1. Erik Mogalian
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  2. Polina German
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Corresponding author

Correspondence to Erik Mogalian.

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Funding disclosure

This study was funded by Gilead Sciences, Inc.

Declaration of conflict of interest

Erik Mogalian, Anita Mathias, Polina German, Cheng Yong Yang, Diana Brainard, John McNally, Lisa Moorehead, and Brian P. Kearney are employees of Gilead Sciences, Inc.

Electronic supplementary material

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Supplemental Fig. 1: Mean (SD) plasma concentration-time profiles following administration ± VEL. a Pravastatin. b Rosuvastatin. c Digoxin

Supplemental Fig. 2 Mean (SD) Plasma VEL Concentration Time-Profiles Following Administration ± Interaction Precipitant. a Rifampin, single-dose (as OATP inhibitor) or cyclosporine. b Ketoconazole. c Rifampin, multiple-dose (as potent inducer)

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Mogalian, E., German, P., Kearney, B.P. et al. Use of Multiple Probes to Assess Transporter- and Cytochrome P450-Mediated Drug–Drug Interaction Potential of the Pangenotypic HCV NS5A Inhibitor Velpatasvir. Clin Pharmacokinet 55, 605–613 (2016). https://doi.org/10.1007/s40262-015-0334-7

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