Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals

Lubomirov, Rubin and Arab-Alameddine, Mona and Rotger, Margalida and Fayet-Mello, Aurélie and Martinez, Raquel and Guidi, Monia and di Iulio, Julia and Cavassini, Matthias and Günthard, Huldrych F. and Furrer, Hansjakob and Marzolini, Catia and Bernasconi, Enos and Calmy, Alexandra and Buclin, Thierry and Decosterd, Laurent A. and Csajka, Chantal and Telenti, Amalio and Swiss HIV Cohort Study, . (2013) Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals. Pharmacogenetics and Genomics, 23 (1). pp. 9-18.

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Official URL: https://edoc.unibas.ch/69520/

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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.; 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.; 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.; 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.
Faculties and Departments:03 Faculty of Medicine > Bereich Medizinische Fächer (Klinik) > Infektiologie > Infektiologie (Battegay M)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Medizinische Fächer (Klinik) > Infektiologie > Infektiologie (Battegay M)
UniBasel Contributors:Marzolini, Catia
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Lippincott Williams & Wilkins
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:01 Jul 2020 12:27
Deposited On:01 Jul 2020 12:27

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