Program Schedule

823
Evaluation of Drug-Drug Interaction between Asunaprevir and Methadone or Buprenorphine/Naloxone

Session: Poster Abstract Session: Clinical - Clinical Trials
Friday, October 10, 2014
Room: The Pennsylvania Convention Center: IDExpo Hall BC
Posters
  • DV_ID_Week_2014_DDI_ASV_Meth-Bup_poster_06Oct14_Presented_AS_6.pdf (591.0 kB)
  • Background: Asunaprevir (ASV) is a selective NS3 protease inhibitor with in vitro activity vs hepatitis C virus (HCV) GT 1, 4, 5 and 6. Methadone (MET) and buprenorphine (BUP) are opioid analgesics; patients on HCV therapy may also require MET or BUP to treat opioid dependence. The effect of ASV on MET or BUP/naloxone (NLX) pharmacokinetics (PK) was assessed in subjects on stable opioid therapy.

    Methods: An open-label, 2-part study assessed the effect of steady-state ASV on the PK of MET (Part 1, P1) or BUP/NLX (Part 2, P2). Safety/tolerability and pharmacodynamics (PD; opiate withdrawal scales/overdose assessment) were also assessed. Subjects (P1, N=15; P2, N=16) received once daily oral MET (40–120mg) or BUP/NLX (8/2–24/6mg) based on prescribed stable dose throughout, in addition to ASV (100 mg BID) on Days 2–12. Serial PK sampling occurred on Days 1 and 12 up to 24 hours postdose. Non-compartmental PK were derived. Ratios of geometric means (GMR) and 90% confidence intervals (90%CI) for R-MET/S-MET/BUP/norBUP Cmax and AUCTAU with and without ASV were derived from linear mixed effects model on log-transformed data.

    Results: Subjects were aged 20–53 years, mostly white (P1, 87%; P2, 100%) and male (P1, 67%; P2, 75%). All completed the study. No clinically meaningful effect was shown as GMR 90% CIs fell within pre-specified interval (P1, 0.7–1.4; P2, 0.5–2.0). ASV coadministration with MET or BUP/NLX was generally well tolerated (P1, 6 [40%] subjects had 9 generally mild AEs; P2, 7 [44%] subjects had AEs, all mild). ASV had no clinically meaningful effect on the PD of MET or BUP/NLX; 1 patient experienced moderate drug withdrawal syndrome but had mild withdrawal symptoms before the study, therefore the association is unclear.

     

    With ASV

    Adj. Geo. Mean

    W/O ASV

    Adj. Geo. Mean

    GMR

    (90%CI)

    R-METa       Cmax, ng/mL

    116.2

    120.2

    0.97 (0.86,1.08)

                          AUCTAU, ng•h/mL

    1757.7

    1924.2

    0.91 (0.82,1.01)

    BUP             Cmax

    4.5

    5.3

    0.85 (0.71,1.01)

                          AUCTAU

    36.1

    37.1

    0.97 (0.73,1.30)

    NORBUP    Cmax

    2.1

    1.8

    1.17 (0.96,1.42)

                          AUCTAU

    33.0

    30.1

    1.10 (0.72,1.68)

    aS-MET and total MET results similar
    Exposures were normalized to lowest dose of MET or BUP.

    Conclusion: Steady-state administration of ASV 100 mg BID had no clinically meaningful effect on the PK of MET or BUP/NLX and was generally well tolerated, suggesting that no dose adjustments are required.

    Tushar Garimella, PhD1, Timothy Eley, PhD1, Bing He, PhD.1, Wen-Lin Luo, PhD, MSc2, Jane Crowell, RN1, Hamza Kandoussi, MSc2, Michael Demicco, MD3, Elizabeth Colston1, Richard Bertz, PhD1 and Marc Bifano, MS1, (1)Research & Development, Bristol-Myers Squibb, Hopewell, NJ, (2)Bristol-Myers Squibb Research & Development, Lawrenceville, NJ, (3)Anaheim Clinical Trials, Anaheim, CA

    Disclosures:

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

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

    B. He, Bristol-Myers Squibb: Employee, Salary

    W. L. Luo, Bristol]Myers Squibb: Employee, Salary

    J. Crowell, Bristol-Myers Squibb: Employee, Salary

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

    M. Demicco, None

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

    R. Bertz, Bristol-Myers Squibb: Employee, 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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