Meta-analysis of the effect of <i>CYP2B6, CYP2A6, UGT2B7</i> and <i>CAR</i> polymorphisms on efavirenz plasma concentrations

Ayuso, Pedro, Neary, Megan ORCID: 0000-0002-4960-2139, Chiong, Justin ORCID: 0000-0001-8063-6399 and Owen, Andrew ORCID: 0000-0002-9819-7651
(2019) Meta-analysis of the effect of <i>CYP2B6, CYP2A6, UGT2B7</i> and <i>CAR</i> polymorphisms on efavirenz plasma concentrations. JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, 74 (11). pp. 3281-3290.

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<h4>Background</h4>Efavirenz primary metabolism is catalysed by CYP2B6 with minor involvement of CYP2A6. Subsequently, phase I metabolites are conjugated by UGT2B7, and constitutive androstane receptor (CAR) has been shown to transcriptionally regulate many relevant enzymes and transporters. Several polymorphisms occurring in the genes coding for these proteins have been shown to impact efavirenz pharmacokinetics in some but not all studies.<h4>Objectives</h4>A meta-analysis was performed to assess the overall effect of CYP2B6 rs3745274, CYP2A6 (rs28399454, rs8192726 and rs28399433), UGT2B7 (rs28365062 and rs7439366) and NR1I3 (rs2307424 and rs3003596) polymorphisms on mid-dose efavirenz plasma concentrations.<h4>Methods</h4>Following a literature review, pharmacokinetic parameters were compiled and a meta-analysis for these variants was performed using Review Manager and OpenMetaAnalyst. A total of 28 studies were included.<h4>Results</h4>Unsurprisingly, the analysis confirmed that individuals homozygous for the T allele for CYP2B6 rs3745274 had significantly higher efavirenz concentrations than those homozygous for the G allele [weighted standard mean difference (WSMD) = 2.98; 95% CI 2.19-3.76; P < 0.00001]. A subgroup analysis confirmed ethnic differences in frequency but with a similar effect size in each ethnic group (P = 0.96). Associations with CYP2A6 and UGT2B7 variants were not statistically significant, but T homozygosity for CAR rs2307424 was associated with significantly lower efavirenz concentrations than in C homozygotes (WSMD = -0.32; 95% CI -0.59 to -0.06; P = 0.02).<h4>Conclusions</h4>This meta-analysis provides the overall effect size for the impact of CYP2B6 rs3745274 and NR1I3 rs2307424 on efavirenz pharmacokinetics. The analysis also indicates that some previous associations were not significant when interrogated across studies.

Item Type: Article
Uncontrolled Keywords: Humans, HIV Infections, Alkynes, Cyclopropanes, Benzoxazines, Metalloendopeptidases, Glucuronosyltransferase, Reverse Transcriptase Inhibitors, Anti-HIV Agents, Polymorphism, Single Nucleotide, Genetic Variation, Cytochrome P-450 CYP2A6, Cytochrome P-450 CYP2B6, ATPases Associated with Diverse Cellular Activities, Constitutive Androstane Receptor
Depositing User: Symplectic Admin
Date Deposited: 03 Jul 2019 07:23
Last Modified: 14 Oct 2023 09:33
DOI: 10.1093/jac/dkz329
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