Program Schedule

1166
Evaluation of Drug-Drug Interaction between Daclatasvir and Methadone or Buprenorphine/Naloxone

Session: Poster Abstract Session: Viral Infections: Treatment and Prevention
Friday, October 10, 2014
Room: The Pennsylvania Convention Center: IDExpo Hall BC
Posters
  • 1014036 4612554-4_IDW_Evaluation_Garimella_Poster_PRINT.pdf (300.7 kB)
  • Background:

    Daclatasvir (DCV) is a potent hepatitis C Virus (HCV) NS5A replication complex inhibitor with pangenotypic (1-6) activity in vitro. Methadone (MET) and buprenorphine (BUP) are opioid medications to treat opioid addiction; patients on HCV therapy may require MET or BUP treatment. The effect of DCV on the pharmacokinetics (PK) of MET or BUP/naloxone (NLX) was assessed in subjects on stable MET or BUP.

    Methods:

    An open-label, 2-part study assessed the effect of steady-state oral administration of DCV on the PK of MET (Part 1, P1) or BUP/NAL (Part 2, P2). Safety/tolerability and pharmacodynamics (PD, opioid withdrawal scales/overdose assessment) were also assessed. Subjects (P1, N=14; P2, N=11) received daily single-dose oral MET (40-120mg) or BUP/NLX (8/2-24/6mg) based on their prescribed stable dose throughout, in addition to DCV (60 mg QD) on Days 2-9. Serial PK sampling occurred predose and postdose till 24 hrs on Day 1 (MET/BUP) and Day 10 (MET/BUP/DCV). Non-compartmental PK were derived. Geometric mean ratios (GMR) and 90% confidence intervals (90%CI) for MET/BUP/norBUP Cmax and AUCTAU were derived from linear mixed effects models.

    Results:

    Subjects were aged 19 to 39 years, mostly white (P1, 93%; P2, 100%) and male (P1, 71%; P2, 91%). All subjects completed the study. No clinically meaningful effect was demonstrated as the GMR and 90% CIs fell within the pre-specified interval (P1, 0.7-1.4; P2, 0.5-2.0: see Table). DCV coadministration was well tolerated: overall, 6 [43%] subjects had AEs (all mild and resolved without treatment). DCV had no clinically significant effect on the PD of MET or BUP/NLX.

     

    With DCV

    Adj. Geo. Mean

    W/O DCV

    Adj. Geo. Mean

    GMR

    (90%CI)

    R-METa       Cmax, ng/mL

    103.6

    96.6

    1.07 (0.97,1.18)

                          AUCTAU, ng•h/mL

    1699.6

    1569.8

    1.08 (0.94,1.24)

    BUP             Cmax, ng/mL

    3.3

    2.5

    1.30 (1.03,1.64)

                          AUCTAU, ng•h/mL

    25.1

    19.2

    1.31 (1.15,1.48)

    NORBUP    Cmax, ng/mL

    3.1

    1.8

    1.65 (1.38,1.99)

                          AUCTAU, ng•h/mL

    42.6

    26.4

    1.62 (1.33,1.96)

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

    Conclusion:

    Steady-state administration of DCV 60 mg QD had no clinically meaningful effect on the PK of MET or BUP/NLX and was generally well tolerated, suggesting that no dose adjustments will be required.

    Tushar Garimella, PhD1, Reena Wang, MD2, Wen-Lin Luo, PhD, MSc3, Philip Wastall, BSc2, Hamza Kandoussi, MSc3, Michael Demicco, MD4, Robert Bruce, MD, MA, MSc5, Carey Hwang, MD, PhD6, Richard Bertz, PhD1 and Marc Bifano, MS1, (1)Research & Development, Bristol-Myers Squibb, Hopewell, NJ, (2)Research and Development, Bristol-Myers Squibb Research & Development, Hopewell, NJ, (3)Bristol-Myers Squibb Research & Development, Lawrenceville, NJ, (4)Anaheim Clinical Trials, Anaheim, CA, (5)Yale University, New Haven, CT, (6)R & D, Bristol-Myers Squibb Research & Development, Hopewell, NJ

    Disclosures:

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

    R. Wang, Bristol]Myers Squibb: Employee, Salary

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

    P. Wastall, Bristol]Myers Squibb: Employee, Salary

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

    M. Demicco, None

    R. Bruce, None

    C. Hwang, 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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