Belkhir Leïla, Elens Laure, Zech Francis, Panin Nadtha, Vincent Anne, Yombi Jean Cyr, Vandercam Bernard, Haufroid Vincent
AIDS Reference Center, Department of Internal Medicine, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
Louvain centre for Toxicology and Applied Pharmacology, Institut de recherche expérimentale et clinique, Université catholique de Louvain, Brussels, Belgium.
PLoS One. 2016 Oct 27;11(10):e0165631. doi: 10.1371/journal.pone.0165631. eCollection 2016.
To assess the impact of the loss-of-function CYP3A5*3 allele (rs776746, 6986A>G SNP) on darunavir (DRV) plasma concentrations.
135 HIV-1 infected patients treated with DRV-based therapy were included in the study and plasma samples were obtained immediately before drug intake in order to determine DRV trough concentrations using an ultra performance liquid chromatography method (UPLC) with diode-array detection (DAD). Noteworthy is the fact that in 16 (11.9%) patients, etravirine (ETR) was combined with DRV. CYP3A5 genotypes were determined using real time PCR method (TaqMan® genotyping assay). The patients were then classified into CYP3A5 expressors (CYP3A51 allele carriers) and non-expressors (CYP3A53 homozygous). Subsequently, the association between DRV plasma trough concentration ([DRV]plasma) and CYP3A5 genotype-based expression status was analyzed.
45% of the patients were classified as CYP3A5 expressors. In the whole cohort, mean [DRV]plasma was not different between CYP3A5 expressors and non-expressors (1894ng/ml [CI95%: 1566-2290] versus 1737ng/ml [CI95%: 1468-2057], p = 0.43). However, in the subgroup of the 16 patients receiving DRV combined with ETR, a significantly lower [DRV]plasma was observed for CYP3A5 expressors when compared to non-expressors (1385ng/ml [CI95%:886.3-2165] versus 3141ng/ml [CI95%:2042-4831], p = 0.007).
Interaction between DRV and ETR is partly mediated by CYP3A5 polymorphism with lower DRV plasma trough concentrations in CYP3A5 expressors suggesting a specific ETR-driven CYP3A5 activation only in CYP3A5 expressors. Consequently, these patients might be more at risk of infra-therapeutic [DRV]plasma. This potentially important observation is a good illustration of a genotype-based drug interaction, which could also have considerable consequences if translated to other CYP3A5-metabolized drugs. Further investigations are thus needed to confirm this association and to explore its clinical impact, mainly in the African population among whom CYP3A5 expressors are more frequent, before recommending systematic CYP3A5 pre-emptive genotyping for DRV-ETR co-administration.
评估功能缺失型CYP3A5*3等位基因（rs776746，6986A>G单核苷酸多态性）对达芦那韦（DRV）血浆浓度的影响。
135例接受基于DRV治疗的HIV-1感染患者纳入本研究，在服药前即刻采集血浆样本，采用超高效液相色谱法（UPLC）结合二极管阵列检测（DAD）测定DRV谷浓度。值得注意的是，16例（11.9%）患者中，依曲韦林（ETR）与DRV联合使用。采用实时PCR法（TaqMan®基因分型检测）测定CYP3A5基因型。然后将患者分为CYP3A5表达者（CYP3A51等位基因携带者）和非表达者（CYP3A53纯合子）。随后，分析DRV血浆谷浓度（[DRV]血浆）与基于CYP3A5基因型的表达状态之间的关联。
45%的患者被分类为CYP3A5表达者。在整个队列中，CYP3A5表达者和非表达者之间的平均[DRV]血浆无差异（1894ng/ml[CI95%：1566 - 2290] vs 1737ng/ml[CI95%：1468 - 2057]，p = 0.43）。然而，在16例接受DRV与ETR联合治疗的患者亚组中，与非表达者相比，CYP3A5表达者的[DRV]血浆显著降低（1385ng/ml[CI95%：886.3 - 2165] vs 3141ng/ml[CI95%：2042 - 4831]，p = 0.007）。
DRV与ETR之间的相互作用部分由CYP3A5多态性介导，CYP3A5表达者的DRV血浆谷浓度较低，提示仅在CYP3A5表达者中存在特定的ETR驱动的CYP3A5激活。因此，这些患者可能更易出现低于治疗水平的[DRV]血浆。这一潜在重要观察结果很好地说明了基于基因型的药物相互作用，如果推广到其他CYP3A5代谢的药物，也可能产生相当大的影响。因此，在推荐对DRV - ETR联合给药进行系统性CYP3A5预先基因分型之前，需要进一步研究以证实这种关联并探索其临床影响，主要是在CYP3A5表达者更常见的非洲人群中。
