title: Randomized pharmacokinetic evaluation of different rifabutin doses in African HIV- infected tuberculosis patients on lopinavir/ritonavir-based antiretroviral therapy.
abstract: BACKGROUND
  Pharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin (150 mg daily) in combination with boosted lopinavir (LPV/r), than the previous dose of rifabutin (150 mg three times weekly {tiw}). But there are limited pharmacokinetic data evaluating the higher dose of rifabutin in combination with LPV/r. Sub-optimal dosing can lead to acquired rifamycin resistance (ARR). The plasma concentration of 25-O-desacetylrifabutin (d-RBT), the metabolite of rifabutin, increases in the presence of PIs and may lead to toxicity.
  
  
  RESULTS
  Sixteen patients with TB-HIV co-infection received rifabutin 300 mg QD in combination with tuberculosis chemotherapy (initially pyrazinamide, isoniazid and ethambutol then only isoniazid), and were then randomized to receive isoniazid and LPV/r based ART with rifabutin 150 mg tiw or rifabutin 150 mg daily. The rifabutin dose with ART was switched after 1 month. Serial rifabutin and d-RBT concentrations were measured after 4 weeks of each treatment. The median AUC0-48 and Cmax of rifabutin in patients taking 150 mg rifabutin tiw was significantly reduced compared to the other treatment arms. Geometric mean ratio (90% CI) for AUC0-48 and Cmax was 0.6 (0.5-0.7) and 0.5 (0.4-0.6) for RBT 150 mg tiw compared with RBT 300 mg and 0.4 (0.4-0.4) and 0.5 (0.5-0.6) for RBT 150 mg tiw compared with 150 mg daily. 86% of patients on the tiw rifabutin arm had an AUC0-24 < 4.5 μg.h/mL, which has previously been associated with acquired rifamycin resistance (ARR). Plasma d-RBT concentrations increased 5-fold with tiw rifabutin dosing and 15-fold with daily doses of rifabutin. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities. One case of uveitis (grade 4), occurred in a patient taking rifabutin 300 mg daily prior to starting ART, and grade 3 neutropenia (asymptomatic) was reported in 4 patients. These events were not associated with increases in rifabutin or metabolite concentrations.
  
  
  CONCLUSIONS
  A daily 150 mg dose of rifabutin in combination with LPV/r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR.
  
  
  BACKGROUND
  ClinicalTrials.gov Identifier: NCT00640887.
authors.forename: Suhashni
authors.initials: S
authors.lastname: Naiker
authors.forename: Cathy
authors.initials: C
authors.lastname: Connolly
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.forename: Tracey
authors.initials: T
authors.lastname: Kellerman
authors.forename: Tarylee
authors.initials: T
authors.lastname: Reddy
authors.forename: Anthony
authors.initials: A
authors.lastname: Harries
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.forename: Christian
authors.initials: C
authors.lastname: Lienhardt
authors.affiliation: TB Research Unit, Medical Research Council, Durban, South Africa. alex.pym@k-rith.org.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pym
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D000904:Antibiotics, Antitubercular / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D044383:Black People; D060085:Coinfection / Q000188:drug therapy / Q000378:metabolism; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D019259:Lamivudine / Q000627:therapeutic use; D061466:Lopinavir / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D008297:Male; D009503:Neutropenia / Q000139:chemically induced; D017828:Rifabutin / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D013019:South Africa; D018119:Stavudine / Q000627:therapeutic use; D014376:Tuberculosis / Q000188:drug therapy / Q000378:metabolism; D014605:Uveitis / Q000139:chemically induced
chemical_list: D019380:Anti-HIV Agents; D000904:Antibiotics, Antitubercular; D017828:Rifabutin; D061466:Lopinavir; D019259:Lamivudine; D018119:Stavudine; D007538:Isoniazid