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.

Fig 1

RAL concentrations (circles) versus time standardized for a 400-mg BID dosing in HIV⁺ and HIV⁻ individuals, with population predictions (solid line) and the 95% prediction interval (dashed lines).

Fig 2

Results of the genetic association analysis. (A) Manhattan plot indicating the 96 SNPs analyzed in 8 chromosomes. The y axis represents the negative log of the associated P value. The line indicates the study-wide cutoff for significance, corresponding to a Bonferroni correction of P = 5.21 × 10⁻⁴ (0.05/96). Only one SNP, rs72551330, reached study-wide significance (beta, +1.78; P = 4.18 × 10⁻⁴). (B) Effect of rs72551330 on RAL bioavailability, assuming a dominant model of inheritance (0, homozygous for the reference allele; 1, heterozygous for the rare allele; 2, homozygous for the rare allele). The y axis represents RAL bioavailability. Median values are represented. Each dot is one individual.

Fig 3

Model-based simulations of RAL at 400 mg BID (A) and 800 mg QD (B) in HIV⁺ individuals. Average RAL concentrations (solid line) and 95% prediction intervals (dashed lines) are shown.