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Keywords:

  • CNS side effects;
  • efavirenz;
  • HIV therapy;
  • pharmacogenetics

Aims

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.