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

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.