title: Effect of ketoconazole on ritonavir and saquinavir concentrations in plasma and cerebrospinal fluid from patients infected with human immunodeficiency virus.
abstract: OBJECTIVE
  Our aim was to evaluate the effect of ketoconazole on ritonavir and saquinavir plasma and cerebrospinal fluid (CSF) concentrations.
  
  
  METHODS
  Twelve patients who were human immunodeficiency virus-seropositive and who were receiving 400 mg of ritonavir and 400 mg of saquinavir twice daily completed a nonfasted, two-period, two-group, longitudinal pharmacokinetic study. Blood samples were collected over the daytime 12-hour dosing interval of the protease inhibitors at baseline (period 1, day 0) and after 10 days of coadministration of 200 mg (n = 6) or 400 mg (n = 6) of ketoconazole once daily (period 2, day 10). One set of paired CSF and blood samples was collected between 4 and 5 hours after the dose on both days.
  
  
  RESULTS
  Ketoconazole significantly increased area under the plasma concentration-time curve, plasma concentration at 12 hours after the dose, and half-life of ritonavir by 29% (95% confidence interval (CI), 13%-46%), 62% (95% CI, 37%-92%), and 31% (95% CI, 13%-51%), respectively. Similar increases of 37% (95% CI, 4%-81%), 94% (95% CI, 41%-167%), and 38% (95% CI, 15%-66%), respectively, were observed for these parameters for saquinavir. Ketoconazole significantly elevated ritonavir CSF concentration by 178% (95% CI, 59%-385%), from 2.4 to 6.6 ng/mL, with no change in paired unbound plasma level (26 ng/mL); this led to a commensurate 181% increase (95% CI, 47%-437%) in CSF/plasma unbound ratio. All pharmacokinetic changes were unrelated to ketoconazole dose or plasma exposures. Corresponding changes for saquinavir CSF pharmacokinetics were insignificant (P > .06); saquinavir CSF levels were unmeasurable in 7 patients (<0.2 ng/mL).
  
  
  CONCLUSIONS
  The disproportionate increase in CSF compared with plasma concentrations of ritonavir is consistent with ketoconazole inhibiting both drug efflux from CSF and systemic clearance.
authors.affiliation: Ottawa Hospital Research Institute, and Department of Medicine, The Ottawa Hospital.
authors.forename: Y
authors.initials: Y
authors.lastname: Khaliq
authors.forename: K
authors.initials: K
authors.lastname: Gallicano
authors.forename: S
authors.initials: S
authors.lastname: Venance
authors.forename: S
authors.initials: S
authors.lastname: Kravcik
authors.forename: D W
authors.initials: DW
authors.lastname: Cameron
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000009:adverse effects / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000134:cerebrospinal fluid / Q000188:drug therapy / Q000378:metabolism*; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D006801:Humans; D007654:Ketoconazole / Q000009:adverse effects / Q000494:pharmacology*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D019438:Ritonavir / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D019258:Saquinavir / Q000009:adverse effects / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*
chemical_list: D000935:Antifungal Agents; D017320:HIV Protease Inhibitors; D019258:Saquinavir; D019438:Ritonavir; D007654:Ketoconazole