title: Assessment of drug-drug interactions between daclatasvir and methadone or buprenorphine-naloxone.
abstract: 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 non-HCV-infected subjects receiving methadone (40 to 120 mg; n = 14) or buprenorphine plus naloxone (8 to 24 mg plus 2 to 6 mg; n = 11). No relevant interaction was inferred if the 90% confidence interval (CI) of the geometric mean ratio (GMR) of opioid area under the plasma concentration-time curve over the dosing interval (AUCτ) or maximum concentration in plasma (C max) with versus without daclatasvir was within literature-derived ranges of 0.7 to 1.43 (R- and S-methadone) or 0.5 to 2.0 (buprenorphine and norbuprenorphine). Dose-normalized AUCτ for R-methadone (GMR, 1.08; 90% CI, 0.94 to 1.24), S-methadone (1.13; 0.99 to 1.30), and buprenorphine (GMR, 1.37; 90% CI, 1.24 to 1.52) were within the no-effect range. The norbuprenorphine AUCτ was slightly elevated in the primary analysis (GMR, 1.62; 90% CI, 1.30 to 2.02) but within the no-effect range in a supplementary analysis of all evaluable subjects. Dose-normalized C max 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.
authors.affiliation: Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA tushar.garimella@bms.com.
authors.forename: T
authors.initials: T
authors.lastname: Garimella
authors.affiliation: Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA.
authors.forename: W-L
authors.initials: WL
authors.lastname: Luo
authors.affiliation: Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA.
authors.forename: P
authors.initials: P
authors.lastname: Wastall
authors.affiliation: Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA.
authors.forename: H
authors.initials: H
authors.lastname: Kandoussi
authors.affiliation: Anaheim Clinical Trials, Anaheim, California, USA.
authors.forename: M
authors.initials: M
authors.lastname: DeMicco
authors.affiliation: Cornell Scott-Hill Health Center and Yale University, New Haven, Connecticut, USA.
authors.forename: R D
authors.initials: RD
authors.lastname: Bruce
authors.affiliation: Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA.
authors.forename: C
authors.initials: C
authors.lastname: Hwang
authors.affiliation: Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA.
authors.forename: R
authors.initials: R
authors.lastname: Bertz
authors.affiliation: Bristol-Myers Squibb Research & Development, Princeton, New Jersey, USA.
authors.forename: M
authors.initials: M
authors.lastname: Bifano
mesh_terms: D002047:Buprenorphine / Q000031:analogs & derivatives / Q000737:chemistry; D000069479:Buprenorphine, Naloxone Drug Combination / Q000737:chemistry*; D002219:Carbamates; D004347:Drug Interactions; D007093:Imidazoles / Q000737:chemistry*; D008691:Methadone / Q000737:chemistry*; D011759:Pyrrolidines; D014633:Valine / Q000031:analogs & derivatives
chemical_list: D000069479:Buprenorphine, Naloxone Drug Combination; D002219:Carbamates; D007093:Imidazoles; D011759:Pyrrolidines; D002047:Buprenorphine; C043585:norbuprenorphine; D014633:Valine; C549273:daclatasvir; D008691:Methadone