title: Impact of efavirenz pharmacokinetics and pharmacogenomics on neuropsychological performance in older HIV-infected patients.
abstract: Pharmacokinetics (PK) and pharmacodynamics of efavirenz and its 8-hydroxy metabolite (8-OH-efavirenz) have not been robustly evaluated in older HIV-infected persons.
  
  
  
  We investigated relationships between neuropsychological (NP) performance and efavirenz and 8-OH-efavirenz PK in HIV-infected individuals >50 years of age.
  
  
  
  A cross-sectional study of HIV-infected adults on an efavirenz-containing regimen. The 12 and 18 h post-dose plasma efavirenz and 8-OH-efavirenz were quantified. CYP2B6 polymorphisms were investigated. Participants underwent neuropsychological tests; surveys were used for depression, sleep quality and anxiety. We investigated potential correlations of efavirenz and 8-OH-efavirenz plasma concentrations with NP performance, sleep, depression, anxiety and CYP2B6 polymorphisms.
  
  
  
  Thirty participants (24 men and 6 women) with mean age 57 years (range 50-68). Plasma efavirenz concentrations did not correlate with NP performance; however, higher plasma 8-OH-efavirenz correlated with better learning (P = 0.002), language (P = 0.002) and total NP z-scores (P = 0.003). No correlation was seen for efavirenz or 8-OH-efavirenz with sleep, anxiety or depression. Median 12 and 18 h efavirenz plasma concentrations were 1967 ng/mL (IQR 1476-2394) and 1676 ng/mL (IQR 1120-2062), respectively. Median 12 and 18 h 8-OH-efavirenz plasma concentrations were 378 ng/mL (IQR 223-589) and 384 ng/mL (IQR 216-621), respectively. CYP2B6 G516T was associated with significantly higher plasma efavirenz at 12 and 18 h (P = 0.02) but not worse NP function.
  
  
  
  Better neurocognitive functioning was associated with higher 8-OH-efavirenz but not efavirenz plasma concentrations. No correlation was observed with sleep or depression. These findings point to a need for greater understanding of the metabolic profile of efavirenz and 8-OH-efavirenz in plasma and the CNS and relationships with antiviral effect and neurotoxicity.
authors.affiliation: Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, USA usandkovsky@unmc.edu.
authors.forename: Uriel
authors.initials: U
authors.lastname: Sandkovsky
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Podany
authors.affiliation: Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, USA.|Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Courtney V
authors.initials: CV
authors.lastname: Fletcher
authors.affiliation: Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.affiliation: Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Felton-Coleman
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Lee C
authors.initials: LC
authors.lastname: Winchester
authors.affiliation: Department of Neurology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Robertson
authors.affiliation: Division of Infectious Diseases, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Swindells
mesh_terms: D015526:AIDS Dementia Complex / Q000473:pathology*; D000368:Aged; D000480:Alkynes; D001007:Anxiety / Q000473:pathology; D048588:Benzoxazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003430:Cross-Sectional Studies; D003521:Cyclopropanes; D065702:Cytochrome P-450 CYP2B6 / Q000235:genetics; D003863:Depression / Q000473:pathology; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests; D010597:Pharmacogenetics; D010949:Plasma / Q000737:chemistry; D011110:Polymorphism, Genetic; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012893:Sleep Wake Disorders / Q000473:pathology
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D065702:Cytochrome P-450 CYP2B6; C098320:efavirenz