Program Schedule

822
Effect of Steady State Daclatasvir Plus Asunaprevir on the Single Dose Pharmacokinetics of the P-glycoprotein Substrate Digoxin in Healthy Adult Subjects

Session: Poster Abstract Session: Clinical - Clinical Trials
Friday, October 10, 2014
Room: The Pennsylvania Convention Center: IDExpo Hall BC
Posters
  • 1014036 4612554-10_IDW_Effect_Garimella_Poster_PRINT.pdf (248.6 kB)
  • Background: Daclatasvir (DCV) is a potent hepatitis C virus (HCV) NS5A replication complex inhibitor with pangenotypic (GT 1-6) activity in vitro. Asunaprevir (ASV) is a selective NS3 protease inhibitor with in vitro activity against GT 1, 4, 5 and 6. These two direct-acting antivirals (DAA) are in phase 3 development and regulatory review as a dual-DAA regimen (DCV+ASV) for the treatment of HCV GT 1b. DCV and ASV both inhibit P-glycoprotein (P-gp) and individually increase plasma concentrations of the P-gp substrate digoxin (DIG), increasing DIG Cmax by 65 and 9% and AUCTAU by 27 and 30%, respectively. The combined effect of DCV+ASV on the pharmacokinetics (PK) of DIG was therefore assessed in healthy subjects.

    Methods: A single sequence, open-label, one-way interaction study assessed the effect of steady-state DCV (60 mg QD) plus ASV (100 mg BID [softgel capsule]) on the PK of single-dose 0.25 mg DIG in healthy subjects. Subjects (N=16) received DIG on Day 1 and 16, and DCV+ASV on Days 6–20. Serial samples for DIG plasma concentrations were collected up to 120 h postdose on Day 1 and Day 16. Non-compartmental DIG PK parameters were derived. Geometric mean ratios (GMR) and 90% confidence intervals (90%CI) for DIG Cmax and AUCinf were derived from linear mixed effects models.

    Results: All subjects (69% male, aged 23-45 years) completed the study. DCV+ASV dosed with DIG resulted in a 77% increase in DIG Cmax and a 29% increase in AUCinf (Table). Study drugs were well tolerated; all AEs were mild in intensity except 2 AEs of increased blood creatinine phosphokinase (1 moderate, 1 severe). No AEs were considered study drug-related and all resolved by study end.

     

     

    With DCV+ASV

    Adj. Geo. Mean (90%CI)

    W/O DCV+ASV

    Adj. Geo. Mean (90%CI)

    GMR

    (90%CI)

    DIG Cmax, pg/mL

    1593 (1407, 1803)

    902 (797,1021)

    1.766 (1.504, 2.073)

    DIG AUCinf, pg×h/mL

    23293 (21522, 25209)

    18090 (15818, 20689)

    1.288 (1.197, 1.385)

    Conclusion: DCV and ASV effects on DIG PK are not additive and are similar to DCV alone. Caution is warranted when dosing DCV+ASV with DIG and other P-gp substrates with a narrow therapeutic window; a priori dose modification does not appear to be required. Therapeutic drug monitoring, if available, may be considered.

    Tushar Garimella, PhD1, Robert Adamczyk2, Michele Stonier2, Hamza Kandoussi, MSc3, Michael Hesney2, Elizabeth Colston1, Timothy Eley, PhD1 and Marc Bifano, MS1, (1)Research & Development, Bristol-Myers Squibb, Hopewell, NJ, (2)Bristol-Myers Squibb Research & Development, Hopewell, NJ, (3)Bristol-Myers Squibb Research & Development, Lawrenceville, NJ

    Disclosures:

    T. Garimella, Bristol-Myers Squibb: Employee, Salary

    R. Adamczyk, Bristol-Myers Squibb: Employee and Shareholder, Salary

    M. Stonier, Bristol-Myers Squibb: Employee, Salary

    H. Kandoussi, Bristol-Myers Squibb: Employee, Salary

    M. Hesney, Bristol-Myers Squibb: Employee, Salary

    E. Colston, Bristol-Myers Squibb: Employee, Salary

    T. Eley, Bristol-Myers Squibb: Employee and Shareholder, Salary

    M. Bifano, Bristol-Myers Squibb: Employee, Salary

    Findings in the abstracts are embargoed until 12:01 a.m. EDT, Oct. 8th with the exception of research findings presented at the IDWeek press conferences.

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