Abstract
Introduction
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 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.
Table 1.
Pharmacokinetic parameters and statistical comparisons
| With DCV | W/O DCV | GMR | ||
|---|---|---|---|---|
| Adj. Geo. Mean | Adj. Geo. Mean | (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) | |