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Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals


Arab-Alameddine, Mona; Fayet-Mello, Aurélie; Lubomirov, Rubin; Neely, Michael; di Iulio, Julia; Owen, Andrew; Boffito, Marta; Cavassini, Matthias; Günthard, Huldrych F; Rentsch, Katharina; Buclin, Thierry; Aouri, Manel; Telenti, Amalio; Decosterd, Laurent Arthur; Rotger, Margalida; Csajka, Chantal (2012). Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals. Antimicrobial agents and chemotherapy, 56(6):2959-2966.

Abstract

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

Abstract

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

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21 citations in Scopus®
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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:2012
Deposited On:13 Dec 2012 13:22
Last Modified:07 Dec 2017 17:22
Publisher:American Society for Microbiology
Series Name:Antimicrobial Agents and Chemotherapy
ISSN:0066-4804
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1128/AAC.05424-11
PubMed ID:22371894

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