Neuropsychometric correlates of efavirenz pharmacokinetics and pharmacogenetics following a single oral dose

Abstract

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 600mg dose of efavirenz. Blood samples for pharmacokinetics were drawn serially from 0 to 12h 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 6h post-dose. Subjective CNS symptoms were assessed at 6h 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, P1h=0.01, P2h=0.05, P3h=0.03, P4h=0.01; AUC, P1h=0.04; clearance P1h=0.05, P2h=0.02, P6h=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(0.312h) (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 6h (P=0.07 and 0.06). Decreased drowsiness at 6h 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. © 2012 The British Pharmacological Society.