Evaluation of drug-drug interaction between daclatasvir and methadone or buprenorphine/naloxone.
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 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.


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 Cmax and AUCTAU 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.
Research & Development, Bristol-Myers Squibb, Princeton, NJ, USA.
Tushar
T
Garimella
Research & Development, Bristol-Myers Squibb, Princeton, NJ, USA.
Reena
R
Wang
Research & Development, Bristol-Myers Squibb, Princeton, NJ, USA.
Wen-Lin
WL
Luo
Research & Development, Bristol-Myers Squibb, Princeton, NJ, USA.
Philip
P
Wastall
Research & Development, Bristol-Myers Squibb, Princeton, NJ, USA.
Hamza
H
Kandoussi
Research & Development, Anaheim Clinical Trials, Anaheim, CA, USA.
Michael
M
Demicco
Clinical Investigation, Yale University, New Haven, CT, USA.
Douglas
D
Bruce
Research & Development, Bristol-Myers Squibb, Princeton, NJ, USA.
Carey
C
Hwang
Research & Development, Bristol-Myers Squibb, Princeton, NJ, USA.
Richard
R
Bertz
Research & Development, Bristol-Myers Squibb, Princeton, NJ, USA.
Marc
M
Bifano