Assessment of Drug-Drug Interactions between Daclatasvir and Methadone or Buprenorphine-Naloxone

Abstract

cHepatitis 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 (AUC) 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 AUC 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 AUC 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.

A Review of Daclatasvir Drug–Drug Interactions

“…The DDI studies conducted during the development program of DCV demonstrate that it has few or no clinically relevant DDIs with HCV DAA regimen partners [16–20], first-line antiretrovirals [23–26], immunosuppressants [12], narcotic analgesics [28], gastric acid-reducing agents [35], or other common concomitant medications (e.g., hormonal contraceptives [32], antidepressants [SSRIs; data on file], and benzodiazepine sedatives) [13]. Furthermore, real-world data, although limited, suggest that the regimen of DCV/SOF has a favorable DDI profile, compared with other NS5A inhibitor-based regimens [39].…”

“…The effect of steady-state DCV on the exposure of oral opioids (methadone and buprenorphine/naloxone) administered at stable doses was assessed in non-HCV-infected, opioid-dependent adults in Study AI444-064 [28]. During co-administration, the exposures (AUCs) of DCV and R-methadone (active methadone enantiomer) were unaffected, and clinically insignificant increases in the exposures of buprenorphine (31%) and norbuprenorphine (62%) were observed; the 90% GMRs of opioid AUCs were contained entirely within the literature-derived ranges of no effect (R-methadone, 0.7–1.23; buprenorphine and norbuprenorphine, 0.5–2.0) and no dose adjustments during co-administration were required.…”

“…During co-administration, the exposures (AUCs) of DCV and R-methadone (active methadone enantiomer) were unaffected, and clinically insignificant increases in the exposures of buprenorphine (31%) and norbuprenorphine (62%) were observed; the 90% GMRs of opioid AUCs were contained entirely within the literature-derived ranges of no effect (R-methadone, 0.7–1.23; buprenorphine and norbuprenorphine, 0.5–2.0) and no dose adjustments during co-administration were required. Pharmacodynamic measures of opioid activity were also unaffected [28]. …”

Daclatasvir Plasma Levels in a Cohort of Patients with Hepatitis C Virus Infection Taking Methadone: A Prospective Analysis

“…DAC is a P-glycoprotein substrate and shares with MET CYP3A4 as a major metabolizing enzyme; moreover, MET is also metabolized by CYP2B6 [9]. The common metabolism by CYP3A4 could give a rationale for a possible DDI between the 2 drugs; however, in a study by Garimella et al [4], no DDI was observed. Nevertheless, this study was conducted on healthy individuals with normal liver function.…”

“…In a study by Garimella et al [4] the drug-drug interaction profile between daclatasvir (DCV; 60 mg) and MET was studied in 14 subjects without CHC, observing no significant interaction.…”