Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers.
Details
Serval ID
serval:BIB_00B288FF2A7D
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers.
Journal
Antimicrobial Agents and Chemotherapy
ISSN
1098-6596[electronic], 0066-4804[linking]
Publication state
Published
Issued date
2010
Volume
54
Number
11
Pages
4619-4625
Language
english
Abstract
Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of the UGT1A1 genotype are unknown. Sufficient inhibition could lead to reduced-dose and -cost raltegravir regimens. Nineteen healthy volunteers, age 24 to 51 years, took raltegravir 400 mg twice daily (arm A) and 400 mg plus atazanavir 400 mg once daily (arm B), separated by ?3 days, in a crossover design. After 1 week on each regimen, raltegravir and raltegravir-glucuronide plasma and urine concentrations were measured by liquid chromatography-tandem mass spectrometry in multiple samples obtained over 12 h (arm A) or 24 h (arm B) and analyzed by noncompartmental methods. UGT1A1 promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravir C(tau), or concentration at the end of the dosing interval, for arm B (24 h) versus arm A (12 h). The arm B-to-arm A geometric mean ratios (95% confidence interval, P value) for plasma raltegravir C(tau), area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and raltegravir-glucuronide/raltegravir AUC(0-12) were 0.38 (0.22 to 0.65, 0.001), 1.32 (0.62 to 2.81, 0.45), and 0.47 (0.38 to 0.59, <0.001), respectively. Nine volunteers were heterozygous and one was homozygous for a UGT1A1 reduction-of-function allele, but these were not associated with metabolite formation. Although atazanavir significantly reduced the formation of the glucuronide metabolite, its steady-state boosting of plasma raltegravir did not render the C(tau) with a once-daily raltegravir dose of 400 mg similar to the C(tau) with the standard twice-daily dose. UGT1A1 promoter variants did not significantly influence this interaction.
Keywords
Integrase Inhibitor Raltegravir, Racial Variability, UGT1A1, Polymorphisms, Ritonavir, Promoter, Safety, Single, Virus
Pubmed
Web of science
Open Access
Yes
Create date
09/12/2010 10:30
Last modification date
20/08/2019 12:23