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Neuropsychometric correlates of efavirenz pharmacokinetics and pharmacogenetics following a single oral dose
Author(s) -
Johnson Daniel H.,
Gebretsadik Tebeb,
Shintani Ayumi,
Mayo Gail,
Acosta Edward P.,
Stein C. Michael,
Haas David W.
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2012.04454.x
Subject(s) - pharmacokinetics , efavirenz , medicine , dosing , nonmem , gastroenterology , pharmacology , anesthesia , human immunodeficiency virus (hiv) , family medicine , antiretroviral therapy , viral load
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 CYP 2 B 6 516/983 genotype was determined. Results Pharmacokinetic indices reflecting increased plasma efavirenz exposure were associated with slower non‐dominant hand grooved pegboard task completion ( C max , P 1 h = 0.01, P 2 h = 0.05, P 3 h = 0.03, P 4 h = 0.01; AUC , P 1 h = 0.04; clearance P 1 h = 0.05, P 2 h = 0.02, P 6 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 C max ( 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 C max ( 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 C max during initial dosing may decrease CNS side effects.