Pharmacokinetic and Pharmacodynamic Comparison of Once-Daily Efavirenz (400 mg vs. 600 mg) in Treatment-Naïve HIV-Infected Patients: Results of the ENCORE1 Study

Clin Pharmacol Ther. 2015 Oct;98(4):406-16. doi: 10.1002/cpt.156. Epub 2015 Jul 14.

Abstract

Daily efavirenz 400 mg (EFV400) was virologically noninferior to 600 mg (EFV600) at 48 weeks in treatment-naïve patients. We evaluated EFV400 and EFV600 pharmacokinetics (NONMEM v. 7.2), assessing patient demographics and genetic polymorphisms (CYP2B6, CYP2A6, CYP3A4, NR1I3) as covariates and explored relationships with efficacy (plasma HIV-RNA (pVL) <200 copies/mL) and safety outcomes at 48 weeks in 606 randomized ENCORE1 patients (female = 32%, African = 37%, Asian = 33%; EFV400 = 311, EFV600 = 295). CYP2B6 516G>T/983T>C/CYP2A6*9B/*17 and weight were associated with efavirenz CL/F. Exposure was significantly lower for EFV400 (geometric mean ratio, GMR; 90% confidence interval, CI: 0.73 (0.68-0.78)) but 97% (EFV400) and 98% (EFV600) of evaluable pVL was <200 copies/mL at 48 weeks (P = 0.802). Four of 20 patients with mid-dose concentrations <1.0 mg/L had pVL ≥200 copies/mL (EFV400 = 1; EFV600 = 3). Efavirenz exposure was similar between those with and without efavirenz-related side effects (GMR; 90% CI: 0.95 (0.88-1.02)). HIV suppression was comparable between doses despite significantly lower EFV400 exposure. Comprehensive evaluation of efavirenz pharmacokinetics/pharmacodynamics revealed important limitations in the accepted threshold concentration.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alkynes
  • Anti-HIV Agents / administration & dosage*
  • Anti-HIV Agents / adverse effects
  • Anti-HIV Agents / pharmacokinetics*
  • Aryl Hydrocarbon Hydroxylases / genetics
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Benzoxazines / administration & dosage*
  • Benzoxazines / adverse effects
  • Benzoxazines / pharmacokinetics*
  • Biomarkers / blood
  • 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
  • Genotype
  • HIV / drug effects*
  • HIV / genetics
  • HIV / pathogenicity
  • HIV Infections / diagnosis
  • HIV Infections / drug therapy*
  • HIV Infections / virology
  • Humans
  • Male
  • Middle Aged
  • Models, Biological
  • Nonlinear Dynamics
  • Pharmacogenetics
  • Phenotype
  • Polymorphism, Genetic
  • RNA, Viral / blood
  • Reverse Transcriptase Inhibitors / administration & dosage*
  • Reverse Transcriptase Inhibitors / adverse effects
  • Reverse Transcriptase Inhibitors / pharmacokinetics*
  • Treatment Outcome
  • Viral Load
  • Young Adult

Substances

  • Alkynes
  • Anti-HIV Agents
  • Benzoxazines
  • Biomarkers
  • Cyclopropanes
  • RNA, Viral
  • Reverse Transcriptase Inhibitors
  • Aryl Hydrocarbon Hydroxylases
  • CYP2A6 protein, human
  • CYP2B6 protein, human
  • CYP3A43 protein, human
  • Cytochrome P-450 CYP2A6
  • Cytochrome P-450 CYP2B6
  • efavirenz