title: Pharmacokinetic evaluation of rifabutin in combination with lopinavir-ritonavir in patients with HIV infection and active tuberculosis.
abstract: BACKGROUND
  Human immunodeficiency virus (HIV)-associated tuberculosis is difficult to treat, given the propensity for drug interactions between the rifamycins and the antiretroviral drugs. We examined the pharmacokinetics of rifabutin before and after the addition of lopinavir-ritonavir.
  
  
  METHODS
  We analyzed 10 patients with HIV infection and active tuberculosis in a state tuberculosis hospital. Plasma was collected for measurement of rifabutin, the microbiologically active 25-desacetyl-rifabutin, and lopinavir by validated high-performance liquid chromatography assays. Samples were collected 2-4 weeks after starting rifabutin at 300 mg thrice weekly without lopinavir-ritonavir, 2 weeks after the addition of lopinavir-ritonavir at 400 and 100 mg, respectively, twice daily to rifabutin at 150 mg thrice weekly, and (if rifabutin plasma concentrations were below the normal range) 2 weeks after an increase in rifabutin to 300 mg thrice weekly with lopinavir-ritonavir. Noncompartmental and population pharmacokinetic analyses (2-compartment open model) were performed.
  
  
  RESULTS
  Rifabutin at 300 mg without lopinavir-ritonavir produced a low maximum plasma concentration (C(max)) in 5 of 10 patients. After the addition of lopinavir-ritonavir to rifabutin at 150 mg, 9 of 10 had low C(max) values. Eight patients had dose increases to 300 mg of rifabutin with lopinavir-ritonavir. Most free rifabutin (unbound to plasma protein) C(max) values were below the tuberculosis minimal inhibitory concentration. For most patients, values for the area under the plasma concentration-time curve were as low or lower than those associated with treatment failure or relapse and with acquired rifamycin resistance in Tuberculosis Trials Consortium/US Public Health Service Study 23. One of the 10 patients experienced relapse with acquired rifamycin resistance.
  
  
  CONCLUSIONS
  The recommended rifabutin doses for use with lopinavir-ritonavir may be inadequate in many patients. Monitoring of plasma concentrations is recommended.
authors.affiliation: University of Miami School of Medicine, Miami, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Boulanger
authors.forename: Elena
authors.initials: E
authors.lastname: Hollender
authors.forename: Karen
authors.initials: K
authors.lastname: Farrell
authors.forename: Jerry Jean
authors.initials: JJ
authors.lastname: Stambaugh
authors.forename: Diane
authors.initials: D
authors.lastname: Maasen
authors.forename: David
authors.initials: D
authors.lastname: Ashkin
authors.forename: Stephen
authors.initials: S
authors.lastname: Symes
authors.forename: Luis A
authors.initials: LA
authors.lastname: Espinoza
authors.forename: Rafael O
authors.initials: RO
authors.lastname: Rivero
authors.forename: Jenny J
authors.initials: JJ
authors.lastname: Graham
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
mesh_terms: D000328:Adult; D000904:Antibiotics, Antitubercular / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000998:Antiviral Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D011744:Pyrimidinones / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D017828:Rifabutin / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019438:Ritonavir / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014376:Tuberculosis / Q000150:complications* / Q000188:drug therapy*
chemical_list: D000904:Antibiotics, Antitubercular; D000998:Antiviral Agents; D011744:Pyrimidinones; D017828:Rifabutin; D061466:Lopinavir; D019438:Ritonavir