title: Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals.
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.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
authors.forename: Mona
authors.initials: M
authors.lastname: Arab-Alameddine
authors.forename: Aurélie
authors.initials: A
authors.lastname: Fayet-Mello
authors.forename: Rubin
authors.initials: R
authors.lastname: Lubomirov
authors.forename: Michael
authors.initials: M
authors.lastname: Neely
authors.forename: Julia
authors.initials: J
authors.lastname: di Iulio
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
authors.forename: Marta
authors.initials: M
authors.lastname: Boffito
authors.forename: Matthias
authors.initials: M
authors.lastname: Cavassini
authors.forename: Huldrych F
authors.initials: HF
authors.lastname: Günthard
authors.forename: Katharina
authors.initials: K
authors.lastname: Rentsch
authors.forename: Thierry
authors.initials: T
authors.lastname: Buclin
authors.forename: Manel
authors.initials: M
authors.lastname: Aouri
authors.forename: Amalio
authors.initials: A
authors.lastname: Telenti
authors.forename: Laurent Arthur
authors.initials: LA
authors.lastname: Decosterd
authors.forename: Margalida
authors.initials: M
authors.lastname: Rotger
authors.forename: Chantal
authors.initials: C
authors.lastname: Csajka
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019380:Anti-HIV Agents; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D015233:Models, Statistical; D008962:Models, Theoretical; D010597:Pharmacogenetics / Q000379:methods*; D019438:Ritonavir / Q000494:pharmacology* / Q000627:therapeutic use; D055815:Young Adult
chemical_list: D019380:Anti-HIV Agents; D019438:Ritonavir