Infection Pharmacology Group, University of Liverpool, Liverpool, UK.
J Antimicrob Chemother. 2019 Nov 1;74(11):3281-3290. doi: 10.1093/jac/dkz329.
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.
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.
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.
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).
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.
依非韦伦的初级代谢主要由 CYP2B6 催化，CYP2A6 也有少量参与。随后，I 相代谢物与 UGT2B7 结合，而组成型雄烷受体（CAR）已被证明可转录调节许多相关酶和转运蛋白。编码这些蛋白的基因中发生的几种多态性已被证明会影响一些但不是所有研究中依非韦伦的药代动力学。
进行荟萃分析以评估 CYP2B6 rs3745274、CYP2A6（rs28399454、rs8192726 和 rs28399433）、UGT2B7（rs28365062 和 rs7439366）和 NR1I3（rs2307424 和 rs3003596）多态性对中剂量依非韦伦血浆浓度的总体影响。
在文献综述后，编译了药代动力学参数，并使用 Review Manager 和 OpenMetaAnalyst 对这些变体进行了荟萃分析。共纳入 28 项研究。
不出所料，分析证实，CYP2B6 rs3745274 纯合子 T 等位基因的个体比纯合子 G 等位基因的个体具有显著更高的依非韦伦浓度[加权标准均数差（WSMD）=2.98；95%置信区间 2.19-3.76；P<0.00001]。亚组分析证实了不同种族的频率差异，但每个种族的效应大小相似（P=0.96）。与 CYP2A6 和 UGT2B7 变体的关联没有统计学意义，但 CAR rs2307424 的 T 纯合子与 C 纯合子相比，依非韦伦浓度显著降低（WSMD=-0.32；95%置信区间-0.59 至-0.06；P=0.02）。
本荟萃分析提供了 CYP2B6 rs3745274 和 NR1I3 rs2307424 对依非韦伦药代动力学影响的总体效应大小。该分析还表明，当在研究间进行询问时，以前的一些关联并不显著。
