title: Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals.
abstract: OBJECTIVE
  Etravirine (ETV) is metabolized by cytochrome P450 (CYP) 3A, 2C9, and 2C19. Metabolites are glucuronidated by uridine diphosphate glucuronosyltransferases (UGT). To identify the potential impact of genetic and non-genetic factors involved in ETV metabolism, we carried out a two-step pharmacogenetics-based population pharmacokinetic study in HIV-1 infected individuals.
  
  
  METHODS
  The study population included 144 individuals contributing 289 ETV plasma concentrations and four individuals contributing 23 ETV plasma concentrations collected in a rich sampling design. Genetic variants [n=125 single-nucleotide polymorphisms (SNPs)] in 34 genes with a predicted role in ETV metabolism were selected. A first step population pharmacokinetic model included non-genetic and known genetic factors (seven SNPs in CYP2C, one SNP in CYP3A5) as covariates. Post-hoc individual ETV clearance (CL) was used in a second (discovery) step, in which the effect of the remaining 98 SNPs in CYP3A, P450 cytochrome oxidoreductase (POR), nuclear receptor genes, and UGTs was investigated.
  
  
  RESULTS
  A one-compartment model with zero-order absorption best characterized ETV pharmacokinetics. The average ETV CL was 41 (l/h) (CV 51.1%), the volume of distribution was 1325 l, and the mean absorption time was 1.2 h. The administration of darunavir/ritonavir or tenofovir was the only non-genetic covariate influencing ETV CL significantly, resulting in a 40% [95% confidence interval (CI): 13-69%] and a 42% (95% CI: 17-68%) increase in ETV CL, respectively. Carriers of rs4244285 (CYP2C19*2) had 23% (8-38%) lower ETV CL. Co-administered antiretroviral agents and genetic factors explained 16% of the variance in ETV concentrations. None of the SNPs in the discovery step influenced ETV CL.
  
  
  CONCLUSIONS
  ETV concentrations are highly variable, and co-administered antiretroviral agents and genetic factors explained only a modest part of the interindividual variability in ETV elimination. Opposing effects of interacting drugs effectively abrogate genetic influences on ETV CL, and vice-versa.
authors.affiliation: Institute of Microbiology, University Hospital Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Rubin
authors.initials: R
authors.lastname: Lubomirov
authors.forename: Mona
authors.initials: M
authors.lastname: Arab-Alameddine
authors.forename: Margalida
authors.initials: M
authors.lastname: Rotger
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fayet-Mello
authors.forename: Raquel
authors.initials: R
authors.lastname: Martinez
authors.forename: Monia
authors.initials: M
authors.lastname: Guidi
authors.forename: Julia
authors.initials: J
authors.lastname: di Iulio
authors.forename: Matthias
authors.initials: M
authors.lastname: Cavassini
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.forename: Hansjakob
authors.initials: H
authors.lastname: Furrer
authors.forename: Catia
authors.initials: C
authors.lastname: Marzolini
authors.forename: Enos
authors.initials: E
authors.lastname: Bernasconi
authors.forename: Alexandra
authors.initials: A
authors.lastname: Calmy
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.forename: Laurent A
authors.initials: LA
authors.lastname: Decosterd
authors.forename: Chantal
authors.initials: C
authors.lastname: Csajka
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000235:genetics; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics* / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D009570:Nitriles; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D011724:Pyridazines / Q000493:pharmacokinetics* / Q000494:pharmacology; D011743:Pyrimidines; D013557:Switzerland / Q000453:epidemiology; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D017320:HIV Protease Inhibitors; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; C451734:etravirine; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A