title: Determination of rifabutin dosing regimen when administered in combination with ritonavir-boosted atazanavir.
abstract: OBJECTIVE
  Treatment of HIV/tuberculosis (TB) co-infected patients is complex due to drug-drug interactions for these chronic diseases. This study evaluates an intermittent dosing regimen for rifabutin when it is co-administered with ritonavir-boosted atazanavir.
  
  
  METHODS
  A randomized, multiple-dose, parallel-group study was conducted in healthy subjects and these subjects received a daily dose of rifabutin 150 mg (n = 15, reference group) or a twice weekly dose with atazanavir 300 mg/ritonavir 100 mg once daily (n = 18, test group). Serial blood samples were collected at steady-state for pharmacokinetic analysis. Modelling and simulation techniques were utilized, integrating data across several healthy subject studies. This study is known as Study AI424-360 and is registered with ClinicalTrials.gov, number NCT00646776.
  
  
  RESULTS
  The pharmacokinetic parameters (C(max), AUC(24avg) and C(min)) for rifabutin (149%, 48% and 40% increase, respectively) and 25-O-desacteyl rifabutin (6.77-, 9.90- and 10.45-fold increases, respectively) were both increased when rifabutin was co-administered with atazanavir/ritonavir than rifabutin 150 mg once daily alone. The study was stopped because subjects experienced more severe declines in neutrophil counts when rifabutin was given with atazanavir/ritonavir than alone. A post-hoc simulation analysis showed that when rifabutin 150 mg was given three times weekly with atazanavir/ritonavir, the average daily exposure of rifabutin was comparable to rifabutin 300 mg once daily, a dose necessary for reducing rifamycin resistance in HIV/TB co-infected patients.
  
  
  CONCLUSIONS
  The benefits to HIV/TB co-infected patients receiving rifabutin 150 mg three times weekly or every other day may outweigh the risks of neutropenia observed here in non-HIV-infected subjects, provided that patients on combination therapy will be closely monitored for safety and tolerability.
authors.affiliation: Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA. jenny.zhang1@bms.com
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhang
authors.forename: Li
authors.initials: L
authors.lastname: Zhu
authors.forename: Michele
authors.initials: M
authors.lastname: Stonier
authors.forename: John
authors.initials: J
authors.lastname: Coumbis
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Xu
authors.forename: Yaoshi
authors.initials: Y
authors.lastname: Wu
authors.forename: Dilek
authors.initials: D
authors.lastname: Arikan
authors.forename: Awny
authors.initials: A
authors.lastname: Farajallah
authors.forename: Richard
authors.initials: R
authors.lastname: Bertz
mesh_terms: D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D019380:Anti-HIV Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D019540:Area Under Curve; D000069446:Atazanavir Sulfate; D001711:Biotransformation; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000502:physiology; D009842:Oligopeptides / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D011725:Pyridines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D017828:Rifabutin / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D019438:Ritonavir / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use*; D014376:Tuberculosis / Q000150:complications* / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D009842:Oligopeptides; D011725:Pyridines; D017828:Rifabutin; D000069446:Atazanavir Sulfate; D019438:Ritonavir