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Interaction between Darunavir and Etravirine Is Partly Mediated by CYP3A5 Polymorphism.

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Belkhir, Leïla [UCL] Elens, Laure [UCL] Zech, Francis [UCL] Panin, Nadtha [UCL] Vincent, Anne [UCL] Yombi, Jean Cyr [UCL] Vandercam, Bernard [UCL] Haufroid, Vincent [UCL]

(eng) OBJECTIVES: To assess the impact of the loss-of-function CYP3A5*3 allele (rs776746, 6986A>G SNP) on darunavir (DRV) plasma concentrations. METHODS: 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 (CYP3A5*1 allele carriers) and non-expressors (CYP3A5*3 homozygous). Subsequently, the association between DRV plasma trough concentration ([DRV]plasma) and CYP3A5 genotype-based expression status was analyzed. RESULTS: 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). CONCLUSIONS: 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.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2016
Language Anglais
Journal information "PLoS One" - Vol. 11, no. 10, p. e0165631 [1-13] (2016)
Peer reviewed yes
Publisher Public Library of Science ((United States) San Francisco, CA)
e-issn 1932-6203
Publication status Publié
Affiliations UCL - SSS/IREC/LTAP - Louvain Centre for Toxicology and Applied Pharmacology
UCL - SSS/IREC/SLUC - Pôle St.-Luc
UCL - (SLuc) Service de biochimie médicale
UCL - (SLuc) Service de médecine interne et maladies infectieuses (MIMI)
UCL - (SLuc) Centre de prise en charge (H.I.V.)
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Bibliographic reference Belkhir, Leïla ; Elens, Laure ; Zech, Francis ; Panin, Nadtha ; Vincent, Anne ; et. al. Interaction between Darunavir and Etravirine Is Partly Mediated by CYP3A5 Polymorphism.. In: PLoS One, Vol. 11, no. 10, p. e0165631 [1-13] (2016)
Permanent URL http://hdl.handle.net/2078.1/179341