title: Evaluation of the drug interaction between rifabutin and efavirenz in patients with HIV infection and tuberculosis.
abstract: BACKGROUND
  Because of drug-drug interactions mediated by hepatic cytochrome P450, tuberculosis treatment guidelines recommend an increase in rifabutin from 300 mg to 450 or 600 mg when combined with efavirenz-based antiretroviral therapy. To assess this recommendation, rifabutin and efavirenz pharmacokinetic parameters were investigated.
  
  
  METHODS
  Plasma concentrations of rifabutin were determined as a baseline control in 15 patients with tuberculosis and human immunodeficiency virus (HIV) infection who were treated with rifabutin 300 mg and isoniazid 15 mg/kg (up to 900 mg) twice weekly. Rifabutin, isoniazid, and efavirenz concentrations were determined after a median of 21 days (interquartile range, 20-34 days) of daily efavirenz-based antiretroviral therapy with twice-weekly rifabutin 600 mg and isoniazid 15 mg/kg.
  
  
  RESULTS
  The mean rifabutin area under the concentration-time curve (AUC(0-24)) increased 20% from the baseline value (geometric mean, 5.0 vs. 4.2 microg.h/mL; ratio of geometric means, 1.2 [90% confidence interval, 1.0-1.4]). Also, the mean efavirenz AUC(0-24) in the 15 patients taking concomitant rifabutin 600 mg twice-weekly was 10% higher than that in 35 historical subjects with HIV infection who were not taking rifabutin. Efavirenz-based antiretroviral therapy was effective; HIV load decreased 2.6 log copies/mL, and the median CD4+ T cell count increased from 141 to 240 cells/mm3 after a median of 21 days of efavirenz-based antiretroviral therapy. No statistically significant differences in isoniazid pharmacokinetic parameters were found.
  
  
  CONCLUSIONS
  The rifabutin dose increase from 300 mg to 600 mg was adequate to compensate for the efavirenz drug interaction in most patients, and no drug interaction with isoniazid was detected. Efavirenz therapy administered at a standard 600-mg dose achieved adequate plasma concentrations in patients receiving intermittent rifabutin and isoniazid therapy, was generally well tolerated, and demonstrated potent antiretroviral activity.
authors.affiliation: University of Texas Health Science Center San Antonio, TX, USA. weiner@uthscsa.edu
authors.forename: Marc
authors.initials: M
authors.lastname: Weiner
authors.forename: Debra
authors.initials: D
authors.lastname: Benator
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
authors.forename: William
authors.initials: W
authors.lastname: Burman
authors.forename: Andrew
authors.initials: A
authors.lastname: Vernon
authors.forename: Melissa
authors.initials: M
authors.lastname: Engle
authors.forename: Awal
authors.initials: A
authors.lastname: Khan
authors.forename: Zhen
authors.initials: Z
authors.lastname: Zhao
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000097:blood / Q000493:pharmacokinetics*; D000904:Antibiotics, Antitubercular / Q000097:blood / Q000493:pharmacokinetics*; D048588:Benzoxazines; D003521:Cyclopropanes; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010078:Oxazines / Q000097:blood / Q000493:pharmacokinetics*; D017828:Rifabutin / Q000097:blood / Q000493:pharmacokinetics*; D014376:Tuberculosis / Q000097:blood* / Q000150:complications / Q000188:drug therapy*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000904:Antibiotics, Antitubercular; D048588:Benzoxazines; D003521:Cyclopropanes; D010078:Oxazines; D017828:Rifabutin; C098320:efavirenz