765. Drug Interaction Profile of GS-5806
Session: Poster Abstract Session: Antimicrobial Agents: Novel Agents
Friday, October 9, 2015
Room: Poster Hall
Posters
  • Bio Xin DDI IDWeek.pdf (141.3 kB)
  • Background: GS-5806 is an oral antiviral fusion inhibitor under clinical evaluation to treat respiratory syncytial virus infections. This study evaluated drug-drug interactions (DDI) of GS-5806 as a victim.

    Methods: This study consisted of 3 cohorts. Cohort 1 (n=16) evaluated the effect of a single dose of cyclosporine (potent inhibitor of P-gp, OATP1B1/1B3, and BCRP) on the pharmacokinetics (PK) of GS-5806. Cohort 2 (n=15) evaluated the effect of multiple-dose rifampin (strong inducer of CYP3A, moderate inducer of CYP2C8/2C19 and also a P-gp inducer) on GS-5806 PK. Cohort 3 (n=18) evaluated the effect of multiple-dose efavirenz (moderate inducer of CYP3A/2B6) on GS-5806. Serial blood samples were collected for up to 120 hours and plasma concentrations of GS-5806 were determined. Safety was monitored throughout the study. An analysis of variance was fitted to the natural log transformation of PK parameters (AUC and Cmax) and included treatment as a fixed effect and subject as a random effect. Geometric mean ratio and 90% confidence intervals (GMR [90%CI]) for GS-5806 were determined for combination vs. GS-5806 alone dosing.

    Results: GS-5806 PK results are presented in Table 1. Inhibition of P-gp, BCRP, and OATP 1B1/1B3 by cyclosporine resulted in a minor increase in exposure to GS-5806.  Induction of CYP enzymes with rifampin or efavirenz resulted in an 83% or 56% decrease, respectively, in GS-5806 AUCinf. GS-5806 was generally well tolerated with no serious adverse events reported.

    Table 1. Summary of GS-5806 plasma exposures (GMR [90% CI])

    Perpetrator

    Cyclosporine

    Rifampin

    Efavirenz

    GS-5806 Cmax

    111 (104, 117)

    59.7 (56.2, 63.4)

    87.5 (80.7, 94.9)

    GS-5806 AUCinf

    126 (118, 135)

    17.5 (15.9, 19.1)

    44.3 (40.0, 49.0)

    Conclusion: GS-5806 is not a sensitive substrate of P-gp, BCRP, or OATP1B1/1B3 thus drug-drug interactions due to those transporters are unlikely.  In contrast, induction of CYP enzymes by rifampin and efavirenz led to a significant decrease in exposure suggesting that GS-5806 elimination can be affected by CYP-mediated metabolism. Thus strong and moderate inducers of CYP enzymes should be excluded in combination with GS-5806.

    Yan Xin, Ph.D., Seth Toback, M.D., Winnie Weng, PhD, Krysia Grycz, MS, Eugene Eisenberg, PhD, Jonna Weston, MS, Bernard Murray, PhD, Jason Chien, M.D., Srini Ramanathan, PhD and Jeffrey Silverman, PhD, Gilead Sciences, Inc., Foster City, CA

    Disclosures:

    Y. Xin, Gilead Sciences: Employee and Shareholder , Salary

    S. Toback, Gilead Sciences: Employee and Shareholder , Salary

    W. Weng, Gilead Sciences, Inc.: Employee and Shareholder , Salary

    K. Grycz, Gilead Sciences, Inc: Employee and Shareholder , Salary

    E. Eisenberg, Gilead Sciences, Inc.: Employee and Shareholder , Salary

    J. Weston, Gilead Sciences, Inc.: Employee and Shareholder , Salary

    B. Murray, Gilead Sciences, Inc.: Employee and Shareholder , Salary

    J. Chien, Gilead Sciences: Employee and Shareholder , Salary

    S. Ramanathan, Gilead Sciences: Employee and Shareholder , Salary

    J. Silverman, Gilead Sciences, Inc.: Employee and Shareholder , Salary

    Findings in the abstracts are embargoed until 12:01 a.m. PDT, Wednesday Oct. 7th with the exception of research findings presented at the IDWeek press conferences.