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

Lubomirov, Rubin; Arab-Alameddine, Mona; Rotger, Margalida; Fayet-Mello, Aurélie; Martinez, Raquel; Guidi, Monia; di Iulio, Julia; Cavassini, Matthias; Günthard, Huldrych F.; Furrer, Hansjakob; Marzolini, Catia; Bernasconi, Enos; Calmy, Alexandra; Buclin, Thierry; Decosterd, Laurent A.; Csajka, Chantal; Telenti, Amalio (2013). Pharmacogenetics-based population pharmacokinetic analysis of etravirine in HIV-1 infected individuals. Pharmacogenetics and genomics, 23(1), pp. 9-18. Lippincott Williams & Wilkins 10.1097/FPC.0b013e32835ade82

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Objectives: 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. Materials and 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. Conclusion: 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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Infectiology

UniBE Contributor:

Furrer, Hansjakob

Subjects:

600 Technology > 610 Medicine & health

ISSN:

1744-6872

Publisher:

Lippincott Williams & Wilkins

Language:

English

Submitter:

Annelies Luginbühl

Date Deposited:

21 Mar 2014 10:56

Last Modified:

19 Oct 2015 11:17

Publisher DOI:

10.1097/FPC.0b013e32835ade82

Uncontrolled Keywords:

CYP2C9, CYP2C19, etravirine, HIV-infected individuals, NONMEM, pharmacogenetics, pharmacokinetics

BORIS DOI:

10.7892/boris.44348

URI:

https://boris.unibe.ch/id/eprint/44348

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