Model-based approach to characterize efavirenz autoinduction and concurrent enzyme induction with carbamazepine

Antimicrob Agents Chemother. 2009 Jun;53(6):2346-53. doi: 10.1128/AAC.01120-08. Epub 2009 Feb 17.

Abstract

Characterization of the time course and magnitude of enzyme induction due to multiple inducers is important for interpretation of clinical data from drug-drug interaction studies. A population interaction model was developed to quantify efavirenz autoinduction and further induction with concurrent carbamazepine coadministration. Efavirenz concentration data in the absence and presence of carbamazepine following single- and multiple-dose oral administrations in healthy subjects were used for model development. The proposed model was able to describe the time-dependent efavirenz autoinduction and the further induction with carbamazepine when the agents were combined. The estimated population averages of efavirenz oral clearance were 5.5, 9.4, 14.4, and 16.7 liters/h on days 1, 14, and 35 and at steady state for the interaction, respectively, for efavirenz monotherapy for 2 weeks followed by the coadministration of carbamazepine for 3 weeks. The estimated times to 50% of the steady state for efavirenz autoinduction and for the induction resulting from the concurrent administration of efavirenz and carbamazepine were similar (around 10 to 12 days). With this model-based analysis, efavirenz exposures can be projected prior to and at the steady state of induction, allowing a better understanding of the time course and magnitude of enzyme induction.

MeSH terms

  • Adolescent
  • Adult
  • Alkynes
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / biosynthesis
  • Benzoxazines / pharmacokinetics*
  • Benzoxazines / pharmacology*
  • Carbamazepine / pharmacology*
  • Cyclopropanes
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A / biosynthesis
  • Drug Interactions
  • Enzyme Induction / drug effects
  • Female
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Oxidoreductases, N-Demethylating / biosynthesis

Substances

  • Alkynes
  • Benzoxazines
  • Cyclopropanes
  • Carbamazepine
  • Aryl Hydrocarbon Hydroxylases
  • CYP2B6 protein, human
  • Cytochrome P-450 CYP2B6
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Oxidoreductases, N-Demethylating
  • efavirenz