title: Neuropsychometric correlates of efavirenz pharmacokinetics and pharmacogenetics following a single oral dose.
abstract: OBJECTIVE
  To determine pharmacokinetic and pharmacogenomic correlates of efavirenz central nervous system (CNS) side effects following a single dose.
  
  
  METHODS
  Thirty-four healthy HIV-negative African Americans were administered a 600 mg dose of efavirenz. Blood samples for pharmacokinetics were drawn serially from 0 to 12 h post-dose. Neuropsychometric testing with drowsiness visual analogue scale, grooved pegboard and letter digit substitution tests was done the day prior to dosing and at 1, 2, 3, 4 and 6 h post-dose. Subjective CNS symptoms were assessed at 6 h post-dose. Composite CYP2B6 516/983 genotype was determined.
  
  
  RESULTS
  Pharmacokinetic indices reflecting increased plasma efavirenz exposure were associated with slower non-dominant hand grooved pegboard task completion (Cmax , P1 h  = 0.01, P2 h  = 0.05, P3 h  = 0.03, P4 h  = 0.01; AUC, P1 h  = 0.04; clearance P1 h  = 0.05, P2 h  = 0.02, P6 h  = 0.01). In a repeated measures model analysis that adjusted timing of neuropsychometric testing for timing of peak drug concentration, clearance (P < 0.001), AUC(0.312 h) (P = 0.001) and Cmax (P = 0.008) were associated with non-dominant grooved pegboard test performance. CYP2B6 genotype trended to correlate with non-dominant hand grooved pegboard at 4 and 6 h (P = 0.07 and 0.06). Decreased drowsiness at 6 h was associated with higher Cmax (P = 0.02).
  
  
  CONCLUSIONS
  Following a single dose of efavirenz, an association between pharmacokinetics and neuropsychometric performance was discernable. A weaker association between genotype and neurocognitive test performance is likely mediated by effect of genotype on plasma clearance. Strategies that lower Cmax during initial dosing may decrease CNS side effects.
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37204, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Johnson
authors.forename: Tebeb
authors.initials: T
authors.lastname: Gebretsadik
authors.forename: Ayumi
authors.initials: A
authors.lastname: Shintani
authors.forename: Gail
authors.initials: G
authors.lastname: Mayo
authors.forename: Edward P
authors.initials: EP
authors.lastname: Acosta
authors.forename: C Michael
authors.initials: CM
authors.lastname: Stein
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D048588:Benzoxazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics*; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D011597:Psychomotor Performance / Q000187:drug effects*
chemical_list: D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D001189:Aryl Hydrocarbon Hydroxylases; C585599:CYP2B6 protein, human; D065702:Cytochrome P-450 CYP2B6; D010089:Oxidoreductases, N-Demethylating; C098320:efavirenz