Open AccessEvaluation of drug‐drug interaction between daclatasvir and methadone or buprenorphine/naloxone
Author(s) -
Garimella Tushar,
Wang Reena,
Luo WenLin,
Wastall Philip,
Kandoussi Hamza,
Demicco Michael,
Bruce Douglas,
Hwang Carey,
Bertz Richard,
Bifano Marc
Publication year - 2014
Publication title -
journal of the international aids society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.724
H-Index - 62
ISSN - 1758-2652
DOI - 10.7448/ias.17.4.19628
Subject(s) - medicine , daclatasvir , buprenorphine , pharmacokinetics , cmax , (+) naloxone , methadone , tolerability , pharmacology , opioid , pharmacodynamics , anesthesia , hepatitis c virus , adverse effect , virology , virus , receptor , ribavirin
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 used 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. Materials and Methods An open‐label, two‐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 (60mg QD) on Days 2–9. Serial PK sampling occurred predose and postdose till 24 hours on Day 1 (MET/BUP) and Day 10 (MET/BUP/DCV). Noncompartmental PK were derived. Geometric mean ratios (GMR) and 90% confidence intervals (90% CI) for MET/BUP/norBUP C max and AUC TAU were derived from linear mixed effects models. Results Subjects were aged 19–39 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 prespecified interval (P1, 0.7–1.4; P2, 0.5–2.0: see Table 1). DCV coadministration was well‐tolerated: overall, six (43%) subjects had adverse events (AEs) (all mild and resolved without treatment). DCV had no clinically significant effect on the PD of MET or BUP/NLX. Conclusions Steady‐state administration of DCV 60mg 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.