title: Pharmacokinetics of the co-administration of boceprevir and St John's wort to male and female healthy volunteers.
abstract: BACKGROUND
  St John's wort (SJW; Hypericum perforatum) induces CYP3A4 that is involved in the metabolism of the hepatitis C virus (HCV) protease inhibitor boceprevir. Reduced boceprevir exposure and efficacy would contribute to therapeutic failure and increase the risk for resistance development. Boceprevir is co-administered with interferon/ribavirin, and depression has been described frequently in patients undergoing HCV treatment. Patients may purchase over-the-counter herbals to manage depression, and knowing the interaction between SJW and boceprevir is desirable.
  
  
  METHODS
  This Phase I, open-label, three-period, cross-over pharmacokinetic study enrolled healthy males and females who, following consent and screening procedures, were randomized to receive SJW on days 1-14, SJW plus boceprevir (SJW on days 22-35 and together on days 31-35) and boceprevir on days 52-56, separated by 7 day washout periods, or the same treatment in the opposite order. Pharmacokinetic sampling was performed at the end of each phase.
  
  
  RESULTS
  Seventeen (11 female) subjects completed the study and no serious adverse events were reported. Geometric mean ratios (GMRs) and 90% CIs for boceprevir (with SJW versus alone) AUC(0-8), C(max) and C8 were 0.91 (0.87-0.96), 0.94 (0.82-1.07) and 1.00 (0.79-1.27), respectively. GMRs and 90% CIs for hypericin, the active component of SJW, (with boceprevir versus alone) AUC(0-8), C(max) and C(8) were 1.23 (1.10-1.38), 1.32 (1.16-1.52) and 1.37 (1.19-1.58), respectively.
  
  
  CONCLUSIONS
  SJW did not have a clinically significant effect on boceprevir plasma concentrations (or those of its metabolite), suggesting that SJW and boceprevir can be safely co-administered.
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Hospital, London, UK.
authors.forename: Akil
authors.initials: A
authors.lastname: Jackson
authors.affiliation: Department of Infectious Diseases, University of Turin, Turin, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: D'Avolio
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Hospital, London, UK.
authors.forename: Graeme
authors.initials: G
authors.lastname: Moyle
authors.affiliation: Department of Infectious Diseases, University of Turin, Turin, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.affiliation: Department of Infectious Diseases, University of Turin, Turin, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Di Perri
authors.affiliation: Liverpool Bioanalytical Facility, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Else
authors.affiliation: Department of Infectious Diseases, University of Turin, Turin, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Simiele
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Hospital, London, UK.
authors.forename: Gurmit Jagjit
authors.initials: GJ
authors.lastname: Singh
authors.affiliation: Liverpool Bioanalytical Facility, Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.affiliation: St Stephen's Centre, Chelsea and Westminster Hospital, London, UK marta.boffito@chelwest.nhs.uk.
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D004347:Drug Interactions; D004789:Enzyme Activation; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D020902:Hypericum; D008297:Male; D008875:Middle Aged; D010936:Plant Extracts / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010949:Plasma / Q000737:chemistry; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D000998:Antiviral Agents; D010936:Plant Extracts; 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
keywords: depression; drug interactions; hepatitis C