title: Interaction between Darunavir and Etravirine Is Partly Mediated by CYP3A5 Polymorphism.
abstract: OBJECTIVE
  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.
authors: 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.
authors: Leïla
authors: L
authors: Belkhir
authors: Louvain centre for Toxicology and Applied Pharmacology, Institut de recherche expérimentale et clinique, Université catholique de Louvain, Brussels, Belgium.|Integrated PharmacoMetrics, PharmacoGenomics and PharmacoKinetics, Louvain Drug Research Institute, Université catholique de Louvain, Brussels, Belgium.
authors: Laure
authors: L
authors: Elens
authors: AIDS Reference Center, Department of Internal Medicine, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors: Francis
authors: F
authors: Zech
authors: Louvain centre for Toxicology and Applied Pharmacology, Institut de recherche expérimentale et clinique, Université catholique de Louvain, Brussels, Belgium.
authors: Nadtha
authors: N
authors: Panin
authors: AIDS Reference Center, Department of Internal Medicine, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors: Anne
authors: A
authors: Vincent
authors: AIDS Reference Center, Department of Internal Medicine, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors: Jean Cyr
authors: JC
authors: Yombi
authors: AIDS Reference Center, Department of Internal Medicine, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors: Bernard
authors: B
authors: Vandercam
authors: Louvain centre for Toxicology and Applied Pharmacology, Institut de recherche expérimentale et clinique, Université catholique de Louvain, Brussels, Belgium.|Department of Clinical Chemistry, Cliniques universitaires Saint-Luc, Université catholique de Louvain, Brussels, Belgium.
authors: Vincent
authors: V
authors: Haufroid
mesh_terms: D000328:Adult; D051544:Cytochrome P-450 CYP3A / Q000235:genetics*; D000069454:Darunavir / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D004347:Drug Interactions; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011110:Polymorphism, Genetic; D011724:Pyridazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D017320:HIV Protease Inhibitors; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D051544:Cytochrome P-450 CYP3A; D000069454:Darunavir