title: Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes.
abstract: OBJECTIVE
  Efavirenz is widely prescribed for HIV-1 infection, and CYP2B6 polymorphisms 516G→T and 983T→C define efavirenz slow metabolizer genotypes. To identify genetic predictors of higher plasma efavirenz concentrations beyond these two common functional alleles, we characterized associations with mid-dosing interval efavirenz concentrations in 84 HIV-infected adults, all carrying two copies of these major loss-of-function CYP2B6 alleles.
  
  
  METHODS
  Study participants had been randomized to efavirenz-containing regimens in prospective clinical trials and had available plasma efavirenz assay data. Analyses focused on secondary metabolism pathway polymorphisms CYP2A6 -48T→G (rs28399433), UGT2B7 735A→G (rs28365062) and UGT2B7 802T→C (rs7439366). Exploratory analyses also considered 196 polymorphisms and 8 copy number variants in 41 drug metabolism/transport genes. Mid-dosing interval efavirenz concentrations at steady-state were obtained ≥8 h but <19 h post-dose. Linear regression was used to test for associations between polymorphisms and log-transformed efavirenz concentrations.
  
  
  RESULTS
  Increased efavirenz concentrations were associated with CYP2A6 -48T→G in all subjects (P = 3.8 × 10(-4)) and in Black subjects (P = 0.027) and White subjects (P = 0.0011) analysed separately; and with UGT2B7 735 G/G homozygosity in all subjects (P = 0.006) and in Black subjects (P = 0.046) and White subjects (P = 0.062) analysed separately. In a multivariable model, CYP2A6 -48T→G and UGT2B7 735 G/G homozygosity remained significant (P < 0.05 for each). No additional polymorphisms or copy number variants were significantly associated with efavirenz concentrations.
  
  
  CONCLUSIONS
  Among individuals with a CYP2B6 slow metabolizer genotype, CYP2A6 and possibly UGT2B7 polymorphisms contribute to even higher efavirenz concentrations.
authors.affiliation: Vanderbilt University School of Medicine, Nashville, TN, USA david.haas@vanderbilt.edu.
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
authors.affiliation: Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors.forename: Awewura
authors.initials: A
authors.lastname: Kwara
authors.affiliation: Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Richardson
authors.affiliation: Vanderbilt University School of Medicine, Nashville, TN, USA.
authors.forename: Paxton
authors.initials: P
authors.lastname: Baker
authors.affiliation: Washington State University, Pullman, WA, USA.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Papageorgiou
authors.affiliation: University of Alabama at Birmingham, Birmingham, AL, USA.
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
authors.affiliation: University at Buffalo, SUNY, Buffalo, NY, USA.
authors.forename: Gene D
authors.initials: GD
authors.lastname: Morse
authors.affiliation: Washington State University, Pullman, WA, USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Court
mesh_terms: D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000627:therapeutic use; D048588:Benzoxazines / Q000097:blood* / Q000378:metabolism / Q000627:therapeutic use*; D044383:Black People / Q000235:genetics; D003521:Cyclopropanes; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics*; D065695:Cytochrome P-450 CYP2B6 Inducers / Q000097:blood / Q000627:therapeutic use; D005260:Female; D018628:Gene Dosage; D014453:Glucuronosyltransferase / Q000235:genetics; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D018894:Reverse Transcriptase Inhibitors / Q000097:blood / Q000627:therapeutic use; D064210:Secondary Metabolism / Q000187:drug effects*; D044465:White People / Q000235:genetics
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D065695:Cytochrome P-450 CYP2B6 Inducers; D018894:Reverse Transcriptase Inhibitors; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; D065702:Cytochrome P-450 CYP2B6; C491474:UGT2B7 protein, human; D014453:Glucuronosyltransferase; C098320:efavirenz
keywords: antiretroviral therapy; non-nucleoside reverse transcriptase inhibitor; pharmacogenetics; pharmacogenomics; pharmacokinetics
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