title: Efavirenz dosing: influence of drug metabolizing enzyme polymorphisms and concurrent tuberculosis treatment.
abstract: BACKGROUND
  Rifampicin-based tuberculosis (TB) treatment alters efavirenz (EFV) clearance. Polymorphisms in important drug metabolizing enzymes and the implications for EFV dosing were investigated.
  
  
  METHODS
  Trough EFV concentrations (Cmin) were measured in 54 South African black patients. During TB treatment, EFV dose was 600 mg in patients <50 kg or 800 mg if ≥50 kg. Off TB treatment it was 600 mg. Polymorphisms in CYP2B6, CYP2A6 and UGT2B7 enzymes were sequenced. A multivariate generalized estimating equations model was fitted to assess predictors of high median EFV Cmin.
  
  
  RESULTS
  During TB treatment, median EFV Cmin was 3.2 (IQR 2.6-6.3) µg/ml and 3.3 (2.4-9.5) µg/ml in the 800 mg and 600 mg groups, respectively. After TB treatment EFV Cmin was 2.0 (1.4-3.5) µg/ml. Minor allele frequencies for CYP2B6 516G→T, 785A→G, 983T→C, UGT2B7-372G→A, CYP2A6*9B and CYP2A6*17 were 0.31, 0.33, 0.23, 0.29, 0.10 and 0.02, respectively. Haplotypes CYP2B6*6 and CYP2B6*18 were found in 38.9% and 25.9% of patients, respectively. Polymorphisms in all three CYP2B6 genes studied (516T-785G-983C) were present in 11.1% of patients and in this group median EFV Cmin was 19.2 (IQR 9.5-20) µg/ml during and 4.7 (IQR 3.5-5.6) µg/ml after TB treatment. The presence of TB treatment and composite genotypes CYP2B6 516 GT/TT, CYP2B6 983 TC/CC and CYP2A6*9B carrier status predicted median EFV Cmin>4 µg/ml. Adverse events due to high EFV concentrations were rare.
  
  
  CONCLUSIONS
  Because polymorphisms of EFV metabolizing enzymes are frequent and are associated with elevated EFV concentrations in this population, EFV dose increases are unnecessary when concomitant rifampicin-containing TB treatment is prescribed.
authors.affiliation: CAPRISA - Centre for the AIDS Programme of Research in South Africa, University of KwaZulu-Natal, Durban, South Africa. gengiaht1@ukzn.ac.za.
authors.forename: Tanuja N
authors.initials: TN
authors.lastname: Gengiah
authors.forename: Julia H
authors.initials: JH
authors.lastname: Botha
authors.forename: Nonhlanhla
authors.initials: N
authors.lastname: Yende-Zuma
authors.forename: Kogieleum
authors.initials: K
authors.lastname: Naidoo
authors.forename: Salim S
authors.initials: SS
authors.lastname: Abdool Karim
mesh_terms: D000328:Adult; D000480:Alkynes; D000483:Alleles; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D048588:Benzoxazines / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D060085:Coinfection; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy* / Q000235:genetics*; D055815:Young Adult
chemical_list: D000480:Alkynes; D000995:Antitubercular Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz