title: A pharmacokinetic study of intermittent rifabutin dosing with a combination of ritonavir and saquinavir in patients infected with human immunodeficiency virus.
abstract: OBJECTIVE
  Our primary aim was to evaluate the plasma exposures and safety of rifabutin and its active 25-O-desacetyl metabolite during concomitant therapy of intermittent rifabutin dosing regimens with a combination of ritonavir and saquinavir.
  
  
  METHODS
  Twenty-four patients without mycobacterial infection who were human immunodeficiency virus seropositive and who were receiving 400 mg each of ritonavir and saquinavir twice daily participated in a 3-period, 2-group longitudinal pharmacokinetic study. Patients were equally randomized to receive 300 mg of rifabutin every 7 days (group 1) or 150 mg of rifabutin every 3 days (group 2) for 8 weeks. Blood samples were collected over the dosing intervals of the protease inhibitors at baseline (period 1) and of the 3 drugs after 4 weeks (period 2) and 8 weeks (period 3) for HPLC measurement of plasma concentrations of the 3 drugs and 25-O-desacetylrifabutin.
  
  
  RESULTS
  Nineteen patients (group 1, n = 10; group 2, n = 9) completed the study. Five individuals withdrew from the study; 3 of them experienced side effects, and 2 were lost to follow-up. For combined groups, mean saquinavir and ritonavir overall (area under the concentration-time curve [AUC]) and peak (C(max)) plasma exposures averaged over periods 2 and 3 did not change significantly (8% to 19%; P > .05) compared with those in period 1 (90% confidence intervals, -7% to 26% for ritonavir and -2% to 38% for saquinavir). Rifabutin and metabolite AUC and C(max) exposures were stable over the 8 weeks, with intraindividual coefficients of variation of 12% to 19%. Oral clearance of rifabutin was similar in both groups (321 mL/min in group 2 versus 372 mL/min in group 1; P = .34). Rifabutin C(max) values were significantly lower in group 2 (310 ng/mL versus 496 ng/mL in group 1; P = .004). Rifabutin and metabolite predose levels were significantly higher in group 2 (rifabutin: 54 ng/mL versus 17 ng/mL; desacetyl rifabutin: 55 ng/mL versus 28 ng/mL; P < .002).
  
  
  CONCLUSIONS
  Rifabutin exposures were similar at 4 and 8 weeks and had minimal effect on ritonavir and saquinavir exposures. Intermittent rifabutin dosing over 8 weeks provided a safe and manageable regimen for concurrent therapy with a combination of ritonavir and saquinavir.
authors.affiliation: Clinical Investigation Unit, Ottawa Hospital Research Institute, and the Department of Medicine, The Ottawa Hospital, Ontario, Canada. kgallicano@axelson.net
authors.forename: K
authors.initials: K
authors.lastname: Gallicano
authors.forename: Y
authors.initials: Y
authors.lastname: Khaliq
authors.forename: G
authors.initials: G
authors.lastname: Carignan
authors.forename: A
authors.initials: A
authors.lastname: Tseng
authors.forename: S
authors.initials: S
authors.lastname: Walmsley
authors.forename: D W
authors.initials: DW
authors.lastname: Cameron
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000097:blood* / Q000188:drug therapy; D000284:Administration, Oral; D000328:Adult; D000704:Analysis of Variance; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008297:Male; D009164:Mycobacterium Infections / Q000097:blood* / Q000188:drug therapy; D017828:Rifabutin / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage / Q000494:pharmacology*; D019258:Saquinavir / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D000904:Antibiotics, Antitubercular; D017320:HIV Protease Inhibitors; D017828:Rifabutin; D019258:Saquinavir; D019438:Ritonavir