Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites.

Abstract

BACKGROUND:

There are limited data on the pharmacogenetics and pharmacokinetics of the CNS penetration of efavirenz.

OBJECTIVES:

We investigated genetic polymorphisms associated with CSF concentrations of efavirenz and its metabolites and explored the relationships with neurocognitive performance.

METHODS:

We included 47 HIV-infected South African black adults with and without HIV-associated neurocognitive disorder on efavirenz/tenofovir/emtricitabine and collected paired plasma-CSF samples. We considered 2049 SNPs, including SNPs known to affect plasma efavirenz exposure, from potentially relevant genes (ABCC5, ABCG2, ABCB1, SLCO2B1, SCLO1A2, ABCC4, CYP2B6 and CYP2A6) and 880 met a linkage disequilibrium (LD)-pruning threshold.

RESULTS:

We identified 9 slow, 21 intermediate and 17 extensive metabolizers. The CYP2B6 983 genotype in multivariate analyses predicted log10-transformed concentrations of plasma efavirenz (β = 0.38, P = 2.7 × 10-03), plasma 7-hydroxy-efavirenz (β = 0.59, P = 3.7 × 10-03), plasma 8-hydroxy-efavirenz:efavirenz ratio (β = -0.31, P = 1.8 × 10-04) and CSF efavirenz (β = 0.36, P = 0.01). Lower plasma 7-hydroxy-efavirenz concentrations were independently associated with CYP2A6 rs10853742 (β = -0.55, P = 3.5 × 10-05), ABCB1 rs115780656 (β = -0.65, P = 4.1 × 10-05) and CYP2A6 -48A→C (β = -0.59, P = 0.01). CYP2A6 -48A→C was independently associated with higher CSF 8-hydroxy-efavirenz:efavirenz ratio (β = 0.54, P = 0.048). CYP2B6 rs2279345 polymorphism was associated with lower plasma 7-hydroxy-efavirenz:efavirenz ratio in multivariate analyses (P < 0.05). No polymorphisms were associated with CSF:plasma ratios of efavirenz, plasma or CSF concentrations of 8-hydroxy-efavirenz or neurocognitive performance.

CONCLUSIONS:

We identified novel genetic associations with plasma efavirenz, plasma 7-hydroxy-efavirenz, plasma 7-hydroxy-efavirenz:efavirenz ratio, plasma 8-hydroxy-efavirenz:efavirenz ratio, CSF efavirenz and CSF 8-hydroxy-efavirenz:efavirenz ratio.

• Authors: Eric H Decloedt, Phumla Z Sinxadi, Gert U van Zyl, Lubbe Wiesner, Saye Khoo, John A Joska, David W Haas, Gary Maartens
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 74 Issue 3 Pg. 699-709 (03 01 2019) ISSN: 1460-2091 [Electronic] England
• PMID: 30535366 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: [email protected].

Chemical References

• Alkynes
• Anti-HIV Agents
• Benzoxazines
• Cyclopropanes
• Reverse Transcriptase Inhibitors
• efavirenz

Topics

• Adult
• Aged
• Alkynes
• Anti-HIV Agents (metabolism, pharmacokinetics)
• Benzoxazines (metabolism, pharmacokinetics)
• Blood-Brain Barrier (drug effects, metabolism)
• Central Nervous System (drug effects, metabolism)
• Cognition (drug effects)
• Cyclopropanes
• Female
• HIV Infections (drug therapy, genetics, metabolism, virology)
• Humans
• Male
• Middle Aged
• Pharmacogenetics (methods)
• Pharmacogenomic Variants
• Polymorphism, Genetic
• Reverse Transcriptase Inhibitors (metabolism, pharmacokinetics)
• Viral Load
• Young Adult