\Population Pharmacokinetic Analysis and Pharmacogenetics of Raltegravir in HIV-Positive and Healthy Individuals

Division of Clinical Pharmacology and Toxicology, University Hospital Center and University of Lausanne, Lausanne, Switzerland.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 02/2012; 56(6):2959-66. DOI: 10.1128/AAC.05424-11
Source: PubMed


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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