title: A Phase I study to assess the safety, tolerability and pharmacokinetic profile of boceprevir and sildenafil when dosed separately and together, in healthy male volunteers.
abstract: OBJECTIVE
  Boceprevir is a first-generation direct-acting antiviral licensed for the treatment of hepatitis C infection. Sildenafil is an oral therapy for erectile dysfunction. As boceprevir is a potent inhibitor of CYP3A4, potential pharmacokinetic interactions may occur when it is coadministered with sildenafil. The aim of this study was to assess the pharmacokinetic profile of sildenafil and boceprevir when dosed separately and together in healthy volunteers.
  
  
  METHODS
  Thirteen male subjects completed the following study procedures: phase 1 (Day 0), a single dose of 25 mg of sildenafil was administered; washout period (Days 1-9); phase 2 (Days 10-15), 800 mg of boceprevir three times a day was administered; and phase 3 (Day 16), 800 mg of boceprevir and 25 mg of sildenafil were administered. All drugs were administered in the fed state. Intensive pharmacokinetic sampling was undertaken on Days 0, 15 and 16. Differences in the pharmacokinetic parameters of sildenafil, N-desmethyl-sildenafil and boceprevir between phase 3 and the earlier phases were evaluated by changes in the geometric mean ratios (GMRs).
  
  
  RESULTS
  All the drugs were well tolerated with no safety concerns arising. In the presence of boceprevir (phase 3 versus phase 1), the GMR for the plasma Cmax and the AUC24 for sildenafil increased by 1.9-fold (95% CI 1.5-2.4) and 2.7-fold (95% CI 2.1-3.4), respectively, whereas a reduction in the Cmax of N-desmethyl-sildenafil was observed (GMR 0.5, 95% CI 0.4-0.7). No significant changes in boceprevir exposure were observed between phases 3 and 2.
  
  
  CONCLUSIONS
  Exposure of sildenafil is increased in the presence of boceprevir. A dose adjustment of sildenafil is therefore necessary. An initial dose of 25 mg of sildenafil is suggested.
authors.affiliation: Imperial College, Faculty of Medicine, London, UK Department of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust St Mary's Hospital, London, UK b.mora-peris@imperial.ac.uk.
authors.forename: Borja
authors.initials: B
authors.lastname: Mora-Peris
authors.affiliation: Department of Clinical and Molecular Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Else
authors.affiliation: Imperial College, Faculty of Medicine, London, UK Department of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust St Mary's Hospital, London, UK.
authors.forename: David
authors.initials: D
authors.lastname: Goldmeier
authors.affiliation: Imperial College, Faculty of Medicine, London, UK Department of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust St Mary's Hospital, London, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Mears
authors.affiliation: Department of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust St Mary's Hospital, London, UK.
authors.forename: Rosy
authors.initials: R
authors.lastname: Weston
authors.affiliation: Imperial College, Faculty of Medicine, London, UK Department of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust St Mary's Hospital, London, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Cooke
authors.affiliation: Department of Clinical and Molecular Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Saye
authors.initials: S
authors.lastname: Khoo
authors.affiliation: Department of Clinical and Molecular Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: David
authors.initials: D
authors.lastname: Back
authors.affiliation: Imperial College, Faculty of Medicine, London, UK Department of HIV and Genitourinary Medicine, Imperial College Healthcare NHS Trust St Mary's Hospital, London, UK.
authors.forename: Alan
authors.initials: A
authors.lastname: Winston
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D004347:Drug Interactions; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma / Q000737:chemistry; D011392:Proline / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D000068677:Sildenafil Citrate / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D064804:Urological Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D064804:Urological Agents; 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; D000068677:Sildenafil Citrate
keywords: HCV; PK; erectile dysfunction