Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers.
Pharmacokinetics and pharmacogenomics of once-daily raltegravir and atazanavir in healthy volunteers.
复制标题
每日一次的拉替拉韦和阿扎那韦在健康志愿者中的药代动力学和药物基因组学。
DOI：
10.1128/aac.00712-10
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发表时间：
2010
影响因子：
4.9
通讯作者：
Calmy,Alexandra
中科院分区：
文献类型：
--
作者：
Neely,Michael;Decosterd,Laurent;Fayet,Aurélie;Lee,JaniceSooFern;Margol,Ashley;Kanani,Meera;diIulio,Julia;vonSchoen-Angerer,Tido;Jelliffe,Roger;Calmy,Alexandra
Atazanavir inhibits UDP-glucuronyl-transferase-1A1 (UGT1A1), which metabolizes raltegravir, but the magnitude of steady-state inhibition and role of theUGT1A1genotype 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.UGT1A1promoter variants were detected with a commercially available kit and published primers. The primary outcome was the ratio of plasma raltegravirCtau, 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,Pvalue) for plasma raltegravirCtau, area under the concentration-time curve from 0 to 12 h (AUC0-12), and raltegravir-glucuronide/raltegravir AUC0-12were 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 aUGT1A1reduction-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 theCtauwith a once-daily raltegravir dose of 400 mg similar to theCtauwith the standard twice-daily dose.UGT1A1promoter variants did not significantly influence this interaction.
