title: Pharmacokinetic interactions between the hepatitis C virus protease inhibitor boceprevir and ritonavir-boosted HIV-1 protease inhibitors atazanavir, darunavir, and lopinavir.
abstract: BACKGROUND
  Boceprevir represents a new treatment option for hepatitis C (HCV)-infected patients, including those with HCV/human immunodeficiency virus coinfection; however, little is known about pharmacokinetic interactions between boceprevir and antiretroviral drugs.
  
  
  METHODS
  A randomized, open-label study to assess the pharmacokinetic interactions between boceprevir and ritonavir-boosted protease inhibitors (PI/r) was conducted in 39 healthy adults. Subjects received boceprevir (800 mg, 3 times daily) for 6 days and then received PI/r as follows: atazanavir (ATV) 300 mg once daily, lopinavir (LPV) 400 mg twice daily, or darunavir (DRV) 600 mg twice daily, each with ritonavir (RTV) 100 mg on days 10-31, plus concomitant boceprevir on days 25-31.
  
  
  RESULTS
  Boceprevir decreased the exposure of all PI/r, with area under the concentration-time curve [AUC] from time 0 to the time of the last measurable sample geometric mean ratios of 0.65 (90% confidence interval [CI], .55-.78) for ATV/r; 0.66 (90% CI, .60-.72) for LPV/r, and 0.56 (90% CI, .51-.61) for DRV/r. Coadministration with boceprevir decreased RTV AUC during a dosing interval τ (AUC(τ)) by 22%-36%. ATV/r did not significantly affect boceprevir exposure, but boceprevir AUC(τ) was reduced by 45% and 32% when coadministered with LPV/r and DRV/r, respectively. Overall, treatments were well tolerated with no unexpected adverse events.
  
  
  CONCLUSIONS
  Concomitant administration of boceprevir with PI/r resulted in reduced exposures of PI and boceprevir. These drug-drug interactions may reduce the effectiveness of PI/r and/or boceprevir when coadministered.
authors.affiliation: Merck Sharp & Dohme Corp, Oss, The Netherlands. ellen.hulskotte@merck.com
authors.forename: Ellen G J
authors.initials: EG
authors.lastname: Hulskotte
authors.forename: Hwa-Ping
authors.initials: HP
authors.lastname: Feng
authors.forename: Fengjuan
authors.initials: F
authors.lastname: Xuan
authors.forename: Marga G J A
authors.initials: MG
authors.lastname: van Zutven
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Treitel
authors.forename: Eric A
authors.initials: EA
authors.lastname: Hughes
authors.forename: Edward
authors.initials: E
authors.lastname: O'Mara
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Youngberg
authors.forename: John A
authors.initials: JA
authors.lastname: Wagner
authors.forename: Joan R
authors.initials: JR
authors.lastname: Butterton
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000493:pharmacokinetics*; D019540:Area Under Curve; D000069446:Atazanavir Sulfate; D000069454:Darunavir; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D015497:HIV-1 / Q000187:drug effects*; D016174:Hepacivirus / Q000187:drug effects; D006801:Humans; D061466:Lopinavir / Q000493:pharmacokinetics; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000493:pharmacokinetics; D011392:Proline / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D011480:Protease Inhibitors / Q000493:pharmacokinetics*; D011725:Pyridines / Q000493:pharmacokinetics; D019438:Ritonavir / Q000493:pharmacokinetics; D013449:Sulfonamides / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D009842:Oligopeptides; D011480:Protease Inhibitors; D011725:Pyridines; D013449:Sulfonamides; D061466:Lopinavir; D000069446:Atazanavir Sulfate; 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; D019438:Ritonavir; D000069454:Darunavir