Correlates of efavirenz exposure in Chilean patients affected with human immunodeficiency virus reveals a novel association with a polymorphism in the constitutive androstane receptor

Ther Drug Monit. 2013 Feb;35(1):78-83. doi: 10.1097/FTD.0b013e318274197e.

Abstract

Objective: To explore the effect of demographics and single-nucleotide polymorphisms in cytochrome P450 (CYP) 2B6, 2A6, UDP-glucuronosyltransferase (UGT) 2B7, and the constitutive androstane receptor (CAR) genes on efavirenz pharmacokinetics in a Chilean cohort affected with human immunodeficiency virus.

Methods: Timed plasma samples obtained throughout the dosing interval were analyzed for efavirenz concentrations with liquid chromatography/tandem mass spectrometry. DNA from whole-blood samples was used for genetic analysis. Data were analyzed using a Mann-Whitney statistical test; furthermore, a Pearson or Spearman correlation was used. A multivariate analysis was then conducted using multiple linear regression by best subset analysis.

Results: Overall 219 patients were included, 208 patients had measurable efavirenz levels and available genetic samples. The overall median (interquartile range) of efavirenz concentration was 2.6 (2.1-3.7) mcg/mL. In multivariate regression analysis, CYP2B6 516G>T (P < 0.0001) and CAR rs2307424 C>T (P = 0.002) were significantly related to efavirenz plasma concentrations.

Conclusion: This novel association between CAR rs2307424 and efavirenz plasma concentrations now requires validation in other cohorts.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkynes
  • Anti-HIV Agents / administration & dosage*
  • Anti-HIV Agents / blood
  • Anti-HIV Agents / pharmacokinetics
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Benzoxazines / administration & dosage*
  • Benzoxazines / blood
  • Benzoxazines / pharmacokinetics
  • Chile
  • Cohort Studies
  • Cyclopropanes
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2B6
  • Female
  • Glucuronosyltransferase / genetics
  • HIV Infections / blood
  • HIV Infections / drug therapy*
  • HIV Infections / enzymology
  • HIV Infections / genetics*
  • Hispanic Americans
  • Humans
  • Male
  • Oxidoreductases, N-Demethylating / genetics
  • Polymorphism, Single Nucleotide
  • Receptors, Cytoplasmic and Nuclear / genetics*

Substances

  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • Receptors, Cytoplasmic and Nuclear
  • constitutive androstane receptor
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2B6
  • Oxidoreductases, N-Demethylating
  • UGT2B7 protein, human
  • Glucuronosyltransferase
  • efavirenz