Neuropsychometric correlates of efavirenz pharmacokinetics and pharmacogenetics following a single oral dose
Article first published online: 15 MAR 2013
© 2012 The Authors. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 4, pages 997–1006, April 2013
How to Cite
Johnson, D. H., Gebretsadik, T., Shintani, A., Mayo, G., Acosta, E. P., Stein, C. M. and Haas, D. W. (2013), Neuropsychometric correlates of efavirenz pharmacokinetics and pharmacogenetics following a single oral dose. British Journal of Clinical Pharmacology, 75: 997–1006. doi: 10.1111/j.1365-2125.2012.04454.x
- Issue published online: 15 MAR 2013
- Article first published online: 15 MAR 2013
- Accepted manuscript online: 7 SEP 2012 06:05AM EST
- Manuscript Accepted: 26 AUG 2012
- Manuscript Received: 3 FEB 2012
- NIH grants. Grant Numbers: MH-071205, AI-077505, AI-54999, AI-058696, GM-31304, TR-000011
- CNS side effects;
- HIV therapy;
To determine pharmacokinetic and pharmacogenomic correlates of efavirenz central nervous system (CNS) side effects following a single dose.
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.
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).
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.