title: Clinical evaluation of the nelfinavir-rifabutin interaction in patients with tuberculosis and human immunodeficiency virus infection.
abstract: OBJECTIVE
  To characterize the bidirectional interaction between twice-daily nelfinavir and twice-weekly rifabutin and isoniazid in patients with tuberculosis and human immunodeficiency virus (HIV) infection.
  
  
  METHODS
  Prospective cohort study.
  
  
  METHODS
  Three clinical research centers.
  
  
  METHODS
  Seven patients with HIV-related tuberculosis.
  
  
  METHODS
  Rifabutin 300 mg and isoniazid 15 mg/kg (maximum dose 900 mg) twice/week were administered for at least 2 weeks during the continuation phase of tuberculosis treatment. Antiretroviral therapy with nelfinavir 1250 mg twice/day and two nucleoside reverse transcriptase inhibitors was then added.
  
  
  RESULTS
  Patients underwent blood sampling for pharmacokinetic analysis during the continuation phase of tuberculosis therapy and after a median of 21 days after the addition of antiretroviral treatment. When rifabutin was coadministered with nelfinavir, its area under the concentration-time curve from 0-21 hours (AUC(0-21)) increased 22% (geometric mean 5.01 microg.hr/ml [90% confidence interval (CI) 3.25-7.71] with nelfinavir vs 4.10 microg.hr/ml [90% CI 3.18-5.27] without nelfinavir; geometric mean ratio 1.22 [90% CI 0.78-1.92]). Also, the AUC(0-21) for the active metabolite, desacetylrifabutin, increased significantly (geometric mean ratio 3.46, 90% CI 1.84-6.47, p=0.009). In the presence of rifabutin, the pharmacokinetic parameters of nelfinavir and its principal metabolite M8 were similar to those of patients not taking rifabutin. No drug interaction between nelfinavir and isoniazid was detected.
  
  
  CONCLUSIONS
  Coadministration of rifabutin and isoniazid without dosage adjustment during twice-weekly tuberculosis therapy with nelfinavir-based antiretroviral therapy resulted in rifabutin exposures within the acceptable ranges for safety and efficacy. Therefore, this combination is an appropriate option for the simultaneous treatment of tuberculosis and HIV infection when tuberculosis therapy is given twice weekly.
authors.affiliation: Division of Infectious Diseases, Veterans Affairs Medical Center, Washington, D.C. 20422, USA. debra.benator@med.va.gov
authors.forename: Debra A
authors.initials: DA
authors.lastname: Benator
authors.forename: Marc H
authors.initials: MH
authors.lastname: Weiner
authors.forename: William J
authors.initials: WJ
authors.lastname: Burman
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Vernon
authors.forename: Zhen A
authors.initials: ZA
authors.lastname: Zhao
authors.forename: Awal E
authors.initials: AE
authors.lastname: Khan
authors.forename: Brenda E
authors.initials: BE
authors.lastname: Jones
authors.forename: Laurie
authors.initials: L
authors.lastname: Sandman
authors.forename: Melissa
authors.initials: M
authors.lastname: Engle
authors.forename: Claudia
authors.initials: C
authors.lastname: Silva-Trigo
authors.forename: Poe H
authors.initials: PH
authors.lastname: Hsyu
authors.forename: Mark I
authors.initials: MI
authors.lastname: Becker
authors.forename: Charles A
authors.initials: CA
authors.lastname: Peloquin
mesh_terms: D000904:Antibiotics, Antitubercular / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000995:Antitubercular Agents / Q000627:therapeutic use; D019540:Area Under Curve; D015331:Cohort Studies; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy*; D017320:HIV Protease Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use; D008297:Male; D019888:Nelfinavir / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D011446:Prospective Studies; D017828:Rifabutin / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy*
chemical_list: D000904:Antibiotics, Antitubercular; D000995:Antitubercular Agents; D017320:HIV Protease Inhibitors; C495123:hydroxy-t-butylamidenelfinavir; C107196:25-desacetylrifabutin; D017828:Rifabutin; D019888:Nelfinavir; D007538:Isoniazid