Pharmacogenetics-based population pharmacokinetic analysis of efavirenz in HIV-1-infected individuals

Clin Pharmacol Ther. 2009 May;85(5):485-94. doi: 10.1038/clpt.2008.271. Epub 2009 Feb 18.


Besides CYP2B6, other polymorphic enzymes contribute to efavirenz (EFV) interindividual variability. This study was aimed at quantifying the impact of multiple alleles on EFV disposition. Plasma samples from 169 human immunodeficiency virus (HIV) patients characterized for CYP2B6, CYP2A6, and CYP3A4/5 allelic diversity were used to build up a population pharmacokinetic model using NONMEM (non-linear mixed effects modeling), the aim being to seek a general approach combining genetic and demographic covariates. Average clearance (CL) was 11.3 l/h with a 65% interindividual variability that was explained largely by CYP2B6 genetic variation (31%). CYP2A6 and CYP3A4 had a prominent influence on CL, mostly when CYP2B6 was impaired. Pharmacogenetics fully accounted for ethnicity, leaving body weight as the only significant demographic factor influencing CL. Square roots of the numbers of functional alleles best described the influence of each gene, without interaction. Functional genetic variations in both principal and accessory metabolic pathways demonstrate a joint impact on EFV disposition. Therefore, dosage adjustment in accordance with the type of polymorphism (CYP2B6, CYP2A6, or CYP3A4) is required in order to maintain EFV within the therapeutic target levels.

MeSH terms

  • Adult
  • Aged
  • Alkynes
  • Alleles
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacokinetics*
  • Anti-HIV Agents / therapeutic use
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Benzoxazines / administration & dosage
  • Benzoxazines / pharmacokinetics*
  • Benzoxazines / therapeutic use
  • Body Weight
  • Cyclopropanes
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A / genetics
  • Cytochrome P-450 CYP3A / metabolism
  • Dose-Response Relationship, Drug
  • Female
  • HIV Infections / drug therapy
  • HIV Infections / genetics*
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Nonlinear Dynamics
  • Oxidoreductases, N-Demethylating / genetics
  • Oxidoreductases, N-Demethylating / metabolism
  • Pharmacogenetics*
  • Polymorphism, Genetic*


  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • CYP2B6 protein, human
  • CYP3A5 protein, human
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Oxidoreductases, N-Demethylating
  • efavirenz