title: Pharmacokinetic and safety profile of raltegravir and ribavirin, when dosed separately and together, in healthy volunteers.
abstract: BACKGROUND
  Treatment of chronic hepatitis C virus (HCV) infection in HIV-1-co-infected individuals remains challenging due to numerous factors, including drug-drug interactions. The aim of this study was to assess the safety and pharmacokinetic (PK) profile of raltegravir and ribavirin when dosed separately and together.
  
  
  METHODS
  Fourteen healthy volunteers [mean (standard deviation) age 35 (10) years, 71% male] entered this phase 1 PK study and received single-dose ribavirin (800 mg) on day 1 (phase 1). Following a washout period, subjects received raltegravir (400 mg twice daily) on days 15-19 (phase 2) and single-dose ribavirin (800 mg) with raltegravir (400 mg) on day 20 (phase 3). Intensive PK sampling was undertaken on days 1, 19 and 20 and differences in geometric mean ratios (GMRs) for PK parameters between study periods were assessed.
  
  
  RESULTS
  No statistically significant differences in PK parameters were observed for raltegravir between phases 2 and 3. A statistically significant decrease in maximum plasma concentration (C(max)) and an increase in time to maximum plasma concentration (T(max)) were observed for ribavirin in phase 3 compared with phase 1 [GMR (95% confidence interval) 0.79 (0.62-1.00) and 1.39 (1.08-1.78), respectively], whereas no significant differences in other ribavirin PK parameters were observed between study phases. No clinically significant safety concerns were reported.
  
  
  CONCLUSIONS
  The PK profile of ribavirin is altered when administered with raltegravir (reduced C(max) and increased T(max)), with no safety concerns identified. This is unlikely to be of clinical significance or have an impact on the antiviral effects of ribavirin in HIV-1- and HCV-co-infected subjects.
authors.affiliation: Department of HIV and GU Medicine, Imperial College Healthcare NHS Trust, St Mary's Hospital, London W21NY, UK.
authors.forename: J
authors.initials: J
authors.lastname: Ashby
authors.forename: L
authors.initials: L
authors.lastname: Garvey
authors.forename: O W
authors.initials: OW
authors.lastname: Erlwein
authors.forename: H
authors.initials: H
authors.lastname: Lamba
authors.forename: R
authors.initials: R
authors.lastname: Weston
authors.forename: K
authors.initials: K
authors.lastname: Legg
authors.forename: N
authors.initials: N
authors.lastname: Latch
authors.forename: M O
authors.initials: MO
authors.lastname: McClure
authors.forename: L
authors.initials: L
authors.lastname: Dickinson
authors.forename: A
authors.initials: A
authors.lastname: D'Avolio
authors.forename: D
authors.initials: D
authors.lastname: Back
authors.forename: A
authors.initials: A
authors.lastname: Winston
mesh_terms: D000293:Adolescent; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D004359:Drug Therapy, Combination; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D012254:Ribavirin