title: The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis.
abstract: OBJECTIVE
  Drug interactions are of concern when treating patients co-infected with human immunodeficiency virus (HIV) and tuberculosis. Concomitant use of efavirenz (EFV) with the enzyme inducer rifampicin might be expected to increase EFV clearance. We investigated the influence of concomitant tuberculosis treatment on the plasma clearance of EFV.
  
  
  METHODS
  Fifty-eight patients were randomized to receive their EFV-containing antiretroviral therapy either during or after tuberculosis treatment. Steady-state EFV plasma concentrations (n = 209 samples) were measured, 83 in the presence of rifampicin. Data were analyzed using a non-linear mixed effects model, and the model was evaluated using non-parametric bootstrap and visual predictive checks.
  
  
  RESULTS
  The patients had a median age of 32 (range 19-55) years and 43.1% were women. There was a bimodal distribution of apparent clearance, with slow EFV metabolizers accounting for 23.6% of the population and having a metabolic capacity 36.4% of that of the faster metabolizers. Apparent EFV clearance after oral administration in fast metabolizers was 12.9 L/h/70 kg whilst off tuberculosis treatment and 9.1 L/h/70 kg when on tuberculosis treatment. In slow metabolizers, the clearance estimates were 3.3 and 4.7 L/h/70 kg in the presence and absence of TB treatment, respectively. Overall there was a 29.5% reduction in EFV clearance during tuberculosis treatment.
  
  
  CONCLUSIONS
  Unexpectedly, concomitant rifampicin-containing tuberculosis treatment reduced apparent EFV clearance with a corresponding increase in EFV exposure. While the reasons for this interaction require further investigation, cytochrome P450 2B6 polymorphisms in the population studied may provide some explanation.
authors: Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa. gengiaht1@ukzn.ac.za
authors: Tanuja N
authors: TN
authors: Gengiah
authors: Nicholas H G
authors: NH
authors: Holford
authors: Julia H
authors: JH
authors: Botha
authors: Andrew L
authors: AL
authors: Gray
authors: Kogieleum
authors: K
authors: Naidoo
authors: Salim S
authors: SS
authors: Abdool Karim
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000904:Antibiotics, Antitubercular / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D048588:Benzoxazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D001711:Biotransformation / Q000187:drug effects; D003521:Cyclopropanes; D004334:Drug Administration Schedule; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D008875:Middle Aged; D008954:Models, Biological; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013019:South Africa; D014376:Tuberculosis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D000904:Antibiotics, Antitubercular; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; C098320:efavirenz; D012293:Rifampin