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A single-nucleotide polymorphism in CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among HIV-infected women.
Gandhi, Monica; Greenblatt, Ruth M; Bacchetti, Peter; Jin, Chengshi; Huang, Yong; Anastos, Kathryn; Cohen, Mardge; Dehovitz, Jack A; Sharp, Gerald B; Gange, Stephen J; Liu, Chenglong; Hanson, Susan C; Aouizerat, Bradley.
Afiliação
  • Gandhi M; Department of Medicine, University of California, San Francisco, CA, USA. monica.gandhi@ucsf.edu
J Infect Dis ; 206(9): 1453-61, 2012 Nov.
Article em En | MEDLINE | ID: mdl-22927450
ABSTRACT

BACKGROUND:

Efavirenz exhibits marked interindividual variability in plasma levels and toxicities. Prior pharmacogenetic studies usually measure exposure via single plasma levels, examine limited numbers of polymorphisms, and rarely model multiple contributors. We analyzed numerous genetic and nongenetic factors impacting short-term and long-term exposure in a large heterogeneous population of human immunodeficiency virus (HIV)-infected women.

METHODS:

We performed 24-hour intensive pharmacokinetic studies in 111 women receiving efavirenz under actual-use conditions and calculated the area-under-the-concentration-time curve (AUC) to assess short-term exposure; the efavirenz concentration in hair was measured to estimate long-term exposure. A total of 182 single-nucleotide polymorphisms (SNPs) and 45 haplotypes in 9 genes were analyzed in relationship to exposure by use of multivariate models that included a number of nongenetic factors.

RESULTS:

Efavirenz AUCs increased 1.26-fold per doubling of the alanine aminotransferase level and 1.23-fold with orange and/or orange juice consumption. Individuals with the CYP2B6 516TT genotype displayed 3.5-fold increases in AUCs and 3.2-fold increases in hair concentrations, compared with individuals with the TG/GG genotype. Another SNP in CYP2B6 (983TT) and a p-glycoprotein haplotype affected AUCs without substantially altering long-term exposure.

CONCLUSIONS:

This comprehensive pharmacogenomics study showed that individuals with the CYP2B6 516TT genotype displayed >3-fold increases in both short-term and long-term efavirenz exposure, signifying durable effects. Pharmacogenetic testing combined with monitoring of hair levels may improve efavirenz outcomes and reduce toxicities.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxirredutases N-Desmetilantes / Plasma / Hidrocarboneto de Aril Hidroxilases / Fármacos Anti-HIV / Polimorfismo de Nucleotídeo Único / Benzoxazinas / Cabelo Idioma: En Ano de publicação: 2012 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Oxirredutases N-Desmetilantes / Plasma / Hidrocarboneto de Aril Hidroxilases / Fármacos Anti-HIV / Polimorfismo de Nucleotídeo Único / Benzoxazinas / Cabelo Idioma: En Ano de publicação: 2012 Tipo de documento: Article