Population pharmacokinetic analysis of elvitegravir and cobicistat in HIV-1-infected individuals.

Details

Serval ID
serval:BIB_001364580150
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Population pharmacokinetic analysis of elvitegravir and cobicistat in HIV-1-infected individuals.
Journal
The Journal of antimicrobial chemotherapy
Author(s)
Barceló C., Gaspar F., Aouri M., Panchaud A., Rotger M., Guidi M., Cavassini M., Buclin T., Decosterd L.A., Csajka C.
Working group(s)
Swiss HIV Cohort Study
Contributor(s)
Aubert V., Battegay M., Bernasconi E., Böni J., Braun D., Bucher H., Burton-Jeangros C., Calmy A., Cavassini M., Dollenmaier G., Egger M., Elzi L., Fehr J., Fellay J., Furrer H., Fux C., Gorgievski M., Günthard H., Haerry D., Hasse B., Hirsch H., Hoffmann M., Hösli I., Kahlert C., Kaiser L., Keiser O., Klimkait T., Kouyos R., Kovari H., Ledergerber B., Martinetti G., Martinez de Tejada B., Marzolini C., Metzner K., Müller N., Nadal D., Nicca D., Pantaleo G., Rauch A., Regenass S., Rudin C., Schöni-Affolter F., Schmid P., Speck R., Stöckle M., Tarr P., Trkola A., Vernazza P., Weber R., Yerly S.
ISSN
1460-2091 (Electronic)
ISSN-L
0305-7453
Publication state
Published
Issued date
07/2016
Peer-reviewed
Oui
Volume
71
Number
7
Pages
1933-1942
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
Co-formulated elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine is among the preferred regimens for first-line ART. A population approach was used to characterize the pharmacokinetics of elvitegravir and cobicistat and identify individual factors and co-medications influencing their disposition, taking into consideration the interaction between the two compounds.
The study population included 144 HIV-infected individuals who provided 186 and 167 elvitegravir and cobicistat plasma concentrations, respectively. First, distinct NONMEM(®) analyses were conducted for elvitegravir and cobicistat, including individual demographic, clinical and genetic factors as potential covariates. Elvitegravir and cobicistat interaction was then assessed through different inhibitory models. Simulations based on the final model served to compare expected drug concentrations under standard and alternative dosage regimens.
Clearance with between-subject variability was 7.6 L/h [coefficient of variation (CV) 16.6%] and volume of distribution 61 L for elvitegravir and 16.0 L/h (CV 41.9%) and 88.3 L, respectively, for cobicistat. Concomitant administration of non-ritonavir-boosted atazanavir decreased elvitegravir clearance by 35%, likely due to UDP-glucuronosyl transferase (UGT) 1A1 inhibition. Concomitant administration of non-ritonavir-boosted atazanavir and ritonavir-boosted darunavir decreased cobicistat clearance by 47% and 27%, respectively. The final interaction model included cobicistat exposure (AUC0-24) on elvitegravir clearance. Simulations confirmed that a reduced elvitegravir dose of 85 mg co-administered with cobicistat and atazanavir produces a concentration-time course comparable to the standard regimen without atazanavir.
Elvitegravir and cobicistat pharmacokinetic variability appears to be mainly explained by drug-drug interactions that may be encountered in routine clinical practice. In these cases, therapeutic drug monitoring and surveillance for potential toxicities would be justified.

Keywords
Adolescent, Adult, Aged, Anti-HIV Agents/administration & dosage, Anti-HIV Agents/pharmacokinetics, Area Under Curve, Cobicistat/administration & dosage, Cobicistat/pharmacokinetics, Cohort Studies, Computer Simulation, Drug Interactions, Female, HIV Infections/drug therapy, HIV Infections/virology, HIV-1/isolation & purification, Humans, Male, Middle Aged, Models, Statistical, Quinolones/administration & dosage, Quinolones/pharmacokinetics, Young Adult
Pubmed
Web of science
Open Access
Yes
Create date
14/04/2016 16:48
Last modification date
20/08/2019 12:21
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