TY - JOUR
T1 - Impact of efavirenz pharmacokinetics and pharmacogenomics on neuropsychological performance in older HIV-infected patients
AU - Sandkovsky, Uriel
AU - Podany, Anthony T.
AU - Fletcher, Courtney V.
AU - Owen, Andrew
AU - Felton-Coleman, Angela
AU - Winchester, Lee C.
AU - Robertson, Kevin
AU - Swindells, Susan
N1 - Funding Information:
This work was partially presented at the 22nd Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 23-26 February 2015 as Oral Abstract no. 84. We thank Dr Howard Fox for his ongoing support, Deanna Hansen for administrative support and we also thank the participants for their invaluable contribution in research studies. This work was supported by NIH grant P30 MH062261 to Dr Howard Fox.
Publisher Copyright:
© The Author 2016.
PY - 2017/1
Y1 - 2017/1
N2 - Background: Pharmacokinetics (PK) and pharmacodynamics of efavirenz and its 8-hydroxy metabolite (8-OHefavirenz) have not been robustly evaluated in older HIV-infected persons. Objectives: We investigated relationships between neuropsychological (NP) performance and efavirenz and 8-OH-efavirenz PK in HIV-infected individuals > 50 years of age. Methods: 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. Results: 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. Conclusions: 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.
AB - Background: Pharmacokinetics (PK) and pharmacodynamics of efavirenz and its 8-hydroxy metabolite (8-OHefavirenz) have not been robustly evaluated in older HIV-infected persons. Objectives: We investigated relationships between neuropsychological (NP) performance and efavirenz and 8-OH-efavirenz PK in HIV-infected individuals > 50 years of age. Methods: 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. Results: 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. Conclusions: 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.
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U2 - 10.1093/jac/dkw403
DO - 10.1093/jac/dkw403
M3 - Article
C2 - 27655857
AN - SCOPUS:85014570430
VL - 72
SP - 200
EP - 204
JO - Journal of Antimicrobial Chemotherapy
JF - Journal of Antimicrobial Chemotherapy
SN - 0305-7453
IS - 1
ER -