title: Population pharmacokinetic drug-drug interaction pooled analysis of existing data for rifabutin and HIV PIs.
abstract: OBJECTIVE
  Extensive but fragmented data from existing studies were used to describe the drug-drug interaction between rifabutin and HIV PIs and predict doses achieving recommended therapeutic exposure for rifabutin in patients with HIV-associated TB, with concurrently administered PIs.
  
  
  METHODS
  Individual-level data from 13 published studies were pooled and a population analysis approach was used to develop a pharmacokinetic model for rifabutin, its main active metabolite 25-O-desacetyl rifabutin (des-rifabutin) and drug-drug interaction with PIs in healthy volunteers and patients who had HIV and TB (TB/HIV).
  
  
  RESULTS
  Key parameters of rifabutin affected by drug-drug interaction in TB/HIV were clearance to routes other than des-rifabutin (reduced by 76%-100%), formation of the metabolite (increased by 224% in patients), volume of distribution (increased by 606%) and distribution to the peripheral compartment (reduced by 47%). For des-rifabutin, clearance was reduced by 35%-76% and volume of distribution increased by 67%-240% in TB/HIV. These changes resulted in overall increased exposure to rifabutin in TB/HIV patients by 210% because of the effects of PIs and 280% with ritonavir-boosted PIs.
  
  
  CONCLUSIONS
  Given together with non-boosted or ritonavir-boosted PIs, rifabutin at 150 mg once daily results in similar or higher exposure compared with rifabutin at 300 mg once daily without concomitant PIs and may achieve peak concentrations within an acceptable therapeutic range. Although 300 mg of rifabutin every 3 days with boosted PI achieves an average equivalent exposure, intermittent doses of rifamycins are not supported by current guidelines.
authors.affiliation: School of Pharmacy, University of Queensland, Brisbane, Australia Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden s.hennig@uq.edu.au.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hennig
authors.affiliation: Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden.
authors.forename: Elin M
authors.initials: EM
authors.lastname: Svensson
authors.affiliation: Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden.
authors.forename: Ronald
authors.initials: R
authors.lastname: Niebecker
authors.affiliation: Department of Medical Microbiology, University of Pretoria, Pretoria, South Africa.
authors.forename: P Bernard
authors.initials: PB
authors.lastname: Fourie
authors.affiliation: Department of Medicine, University of Texas Health Science Center and Veterans Administration Medical Center, San Antonio, TX, USA.
authors.forename: Marc H
authors.initials: MH
authors.lastname: Weiner
authors.affiliation: Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Bonora
authors.affiliation: College of Pharmacy and Emerging Pathogens Institute, University of Florida, Gainesville, FL, USA.
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.affiliation: Novum Pharmaceutical Research Services, Murrieta, CA, USA.
authors.forename: Keith
authors.initials: K
authors.lastname: Gallicano
authors.affiliation: Johns Hopkins Adult AIDS Clinical Trials Unit, Division of Clinical Pharmacology, Baltimore, MD, USA.
authors.forename: Charles
authors.initials: C
authors.lastname: Flexner
authors.affiliation: Tuberculosis Research Unit, Medical Research Council and KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa.
authors.forename: Alex
authors.initials: A
authors.lastname: Pym
authors.affiliation: Janssen Infectious Diseases BVBA, Beerse, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vis
authors.affiliation: Special Programme for Research and Training in Tropical Diseases (TDR), World Health Organization (WHO), Geneva, Switzerland.
authors.forename: Piero L
authors.initials: PL
authors.lastname: Olliaro
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.affiliation: Department of Pharmaceutical Bioscience, Uppsala University, Uppsala, Sweden.
authors.forename: Mats O
authors.initials: MO
authors.lastname: Karlsson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics / Q000627:therapeutic use*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008875:Middle Aged; D017828:Rifabutin / Q000493:pharmacokinetics / Q000627:therapeutic use*; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy*; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D017320:HIV Protease Inhibitors; D017828:Rifabutin
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