Author:
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,
Abstract
ABSTRACTThe 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*3was 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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
37 articles.
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