title: Pharmacokinetic interaction between HCV protease inhibitor boceprevir and methadone or buprenorphine in subjects on stable maintenance therapy.
abstract: OBJECTIVE
  Intravenous opioid use is a common route of hepatitis C virus (HCV) infection; consequently, the prevalence of HCV is high among patients on methadone or buprenorphine/naloxone. The authors evaluated the pharmacokinetic interaction of boceprevir with methadone or buprenorphine/naloxone in patients on stable maintenance therapy.
  
  
  METHODS
  This was a two-center, open-label, fixed-sequence study in 21 adult volunteers on stable maintenance therapy. Oral methadone (20-150 mg once daily) or sublingual buprenorphine/naloxone (8/2-24/6 mg once daily) was administered alone or in combination with boceprevir (800 mg every 8 h) on days 2-7. Pharmacokinetic sampling occurred before and up to 24 h after the dose on days 1 and 7.
  
  
  RESULTS
  Coadministration of boceprevir reduced the area under the concentration-time curve during a dosing interval τ (AUC τ ) and maximum observed plasma (or serum) concentration (C max) of R-methadone (geometric mean ratios (GMRs) [90 % confidence intervals (CIs)], 0.85 [0.74, 0.96] and 0.90 [0.71, 1.13]) and S-methadone (GMRs [90 % CIs], 0.78 [0.66, 0.93] and 0.83 [0.64, 1.09]). Boceprevir increased the AUC τ and C max of buprenorphine (GMRs [90 % CIs], 1.19 [0.91, 1.58] and 1.18 [0.93, 1.50]) and naloxone (GMRs [90 % CIs], 1.33 [0.90, 1.93] and 1.09 [0.79, 1.51]). Boceprevir exposure upon methadone or buprenorphine/naloxone coadministration was not clinically different from historical controls and there was no evidence of opioid withdrawal or excess.
  
  
  CONCLUSIONS
  There was no clinically meaningful impact of boceprevir on methadone or buprenorphine pharmacokinetics, suggesting that methadone/buprenorphine dose adjustments are not required upon coadministration with boceprevir. Individual patients may differ in their clinical experience and clinicians should maintain vigilance when coadministering these medications.
authors: Department of Clinical Pharmacology, Merck Sharp & Dohme, P. O. Box 20, 53410 BH, Oss, Netherlands.
authors: Ellen G J
authors: EG
authors: Hulskotte
authors: R Douglas
authors: RD
authors: Bruce
authors: Hwa-Ping
authors: HP
authors: Feng
authors: Lynn R
authors: LR
authors: Webster
authors: Feng
authors: F
authors: Xuan
authors: Wen H
authors: WH
authors: Lin
authors: Edward
authors: E
authors: O'Mara
authors: John A
authors: JA
authors: Wagner
authors: Joan R
authors: JR
authors: Butterton
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002047:Buprenorphine / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D000069479:Buprenorphine, Naloxone Drug Combination / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D004347:Drug Interactions; D005260:Female; D006801:Humans; D060046:Maintenance Chemotherapy; D008297:Male; D008691:Methadone / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D008875:Middle Aged; D058850:Opiate Substitution Treatment / Q000009:adverse effects; D011392:Proline / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000069479:Buprenorphine, Naloxone Drug Combination; D011480:Protease Inhibitors; D002047:Buprenorphine; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; D008691:Methadone