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J Antimicrob Chemother. 2014 Aug;69(8):2175-82. doi: 10.1093/jac/dku110. Epub 2014 Apr 11.

Secondary metabolism pathway polymorphisms and plasma efavirenz concentrations in HIV-infected adults with CYP2B6 slow metabolizer genotypes.

Author information

  • 1Vanderbilt University School of Medicine, Nashville, TN, USA david.haas@vanderbilt.edu.
  • 2Warren Alpert Medical School of Brown University, Providence, RI, USA.
  • 3Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 4Washington State University, Pullman, WA, USA.
  • 5University of Alabama at Birmingham, Birmingham, AL, USA.
  • 6University at Buffalo, SUNY, Buffalo, NY, USA.

Abstract

OBJECTIVES:

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.

© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

KEYWORDS:

antiretroviral therapy; non-nucleoside reverse transcriptase inhibitor; pharmacogenetics; pharmacogenomics; pharmacokinetics

PMID:
24729586
[PubMed - in process]
PMCID:
PMC4100708
[Available on 2015/8/1]

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