1Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA firstname.lastname@example.org.
2Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA.
3Anaheim Clinical Trials, Anaheim, California, USA.
4Cornell Scott-Hill Health Center and Yale University, New Haven, Connecticut, USA.
Hepatitis C virus (HCV) infection is common among people who inject drugs, including those managed with maintenance opioids. Pharmacokinetic interactions between opioids and emerging oral HCV antivirals merit evaluation. Daclatasvir is a potent pangenotypic inhibitor of the HCV NS5A replication complex recently approved for HCV treatment in Europe and Japan in combination with other antivirals. The effect of steady-state daclatasvir (60 mg daily) on stable plasma exposure to oral opioids was assessed in HCV-uninfected subjects receiving methadone (40-120 mg; N=14) or buprenorphine plus naloxone (8-24 mg plus 2-6 mg; N=11). No relevant interaction was inferred if the 90% confidence interval (90%CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum plasma concentration (Cmax) with versus without daclatasvir was within literature-derived ranges of 0.7-1.43 (R- and S-methadone) or 0.5-2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR 1.08; 90%CI 0.94-1.24), S-methadone (1.13; 0.99-1.30) and buprenorphine (1.37; 1.24-1.52) were within the no-effect range. Norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR 1.62; 1.30-2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized Cmax for both methadone enantiomers, buprenorphine and norbuprenorphine, were within the no-effect range. Standardized assessments of opioid pharmacodynamics were unchanged throughout daclatasvir administration with methadone or buprenorphine. Daclatasvir pharmacokinetics were similar to historical data. Coadministration of daclatasvir and opioids was generally well tolerated. In conclusion, these data suggest that daclatasvir can be administered with buprenorphine or methadone without dose adjustments.