Population Pharmacokinetic Modeling To Estimate the Contributions of Genetic and Nongenetic Factors to Efavirenz Disposition

Antimicrob Agents Chemother. 2016 Dec 27;61(1):e01813-16. doi: 10.1128/AAC.01813-16. Print 2017 Jan.


Efavirenz pharmacokinetics is characterized by large between-subject variability, which determines both therapeutic response and adverse effects. Some of the variability in efavirenz pharmacokinetics has been attributed to genetic variability in cytochrome P450 genes that alter efavirenz metabolism, such as CYP2B6 and CYP2A6 While the effects of additional patient factors have been studied, such as sex, weight, and body mass index, the extent to which they contribute to variability in efavirenz exposure is inconsistently reported. The aim of this analysis was to develop a pharmacometric model to quantify the contribution of genetic and nongenetic factors to efavirenz pharmacokinetics. A population-based pharmacokinetic model was developed using 1,132 plasma efavirenz concentrations obtained from 73 HIV-seronegative volunteers administered a single oral dose of 600 mg efavirenz. A two-compartment structural model with absorption occurring by zero- and first-order processes described the data. Allometric scaling adequately described the relationship between fat-free mass and apparent oral clearance, as well as fat mass and apparent peripheral volume of distribution. Inclusion of fat-free mass and fat mass in the model mechanistically accounted for correlation between these disposition parameters and sex, weight, and body mass index. Apparent oral clearance of efavirenz was reduced by 25% and 51% in subjects predicted to have intermediate and slow CYP2B6 metabolizer status, respectively. The final pharmacokinetic model accounting for fat-free mass, fat mass, and CYP2B6 metabolizer status was consistent with known mechanisms of efavirenz disposition, efavirenz physiochemical properties, and pharmacokinetic theory. (This study has been registered at ClinicalTrials.gov under identifier NCT00668395.).

Keywords: body composition; cytochrome P450 2B6 (CYP2B6); efavirenz; population pharmacokinetics.

Publication types

  • Clinical Trial

MeSH terms

  • Adipose Tissue / metabolism
  • Administration, Oral
  • Adolescent
  • Adult
  • Alkynes
  • Anti-HIV Agents / pharmacokinetics*
  • Benzoxazines / pharmacokinetics*
  • Biotransformation
  • Body Mass Index
  • Body Weight
  • Cyclopropanes
  • Cytochrome P-450 CYP2A6 / genetics*
  • Cytochrome P-450 CYP2A6 / metabolism
  • Cytochrome P-450 CYP2B6 / genetics*
  • Cytochrome P-450 CYP2B6 / metabolism
  • Drug Administration Schedule
  • Female
  • Gene Expression
  • Healthy Volunteers
  • Humans
  • Male
  • Middle Aged
  • Models, Statistical*
  • Sex Factors
  • Tissue Distribution


  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Cyclopropanes
  • CYP2A6 protein, human
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2B6
  • efavirenz

Associated data

  • ClinicalTrials.gov/NCT00668395