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



Decloedt, Eric H, Sinxadi, Phumla Z, van Zyl, Gert U, Wiesner, Lubbe, Khoo, Saye, Joska, John A, Haas, David W and Maartens, Gary
(2018) Pharmacogenetics and pharmacokinetics of CNS penetration of efavirenz and its metabolites. The Journal of antimicrobial chemotherapy.

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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.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 07 Jan 2019 10:08
Last Modified: 09 Jan 2021 04:30
DOI: 10.1093/jac/dky481
URI: https://livrepository.liverpool.ac.uk/id/eprint/3030898