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首页> 外文期刊>The Journal of Clinical Pharmacology: Official Journal of the American College of Clinical Pharmacology >Lack of a clinically meaningful pharmacokinetic effect of rifabutin on raltegravir: in vitro/in vivo correlation.
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Lack of a clinically meaningful pharmacokinetic effect of rifabutin on raltegravir: in vitro/in vivo correlation.

机译：缺乏利福布汀对拉格韦的临床意义的药代动力学作用：体内/体外相关性。

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摘要

Raltegravir is an HIV-1 integrase strand transfer inhibitor with potent activity against HIV-1. A prior investigation of raltegravir coadministered with rifampin demonstrated a decrease in plasma concentrations of raltegravir likely secondary to induction of UGT1A1, the enzyme primarily responsible for the metabolism of raltegravir. Little is known regarding the induction of UGT1A1 by rifabutin, an alternate rifamycin. In vitro characterization of the induction potency of rifampin and rifabutin on UGT1A1 was performed. In vitro studies indicate that rifabutin is a less potent inducer of UGT1A1 messenger RNA expression than is rifampin. A fixed-sequence, 2-period, clinical crossover study was conducted to assess the effect of rifabutin on plasma levels of raltegravir: period 1, 400 mg of raltegravir every 12 hours for 4 days; period 2, 400 mg of raltegravir every 12 hours and 300 mg of rifabutin once daily for 14 days. Geometric mean ratio (GMR) (coadministration of rifabutin and raltegravir vs raltegravir alone) of raltegravir area under the concentration-time curve from 0 to 12 hours post dose (AUC(0-12h)) and the 90% confidence interval (CI) was 1.19 (0.86-1.63); GMR of concentration at 12 hours (C(12h)) and 90% CI was 0.80 (0.68-0.94); and GMR of time to maximal concentration (C(max)) and 90% CI was 1.39 (0.87-2.21). Overall, coadministration of rifabutin did not alter raltegravir pharmacokinetics to a clinically meaningful degree.
机译：Raltegravir是一种HIV-1整合酶链转移抑制剂，对HIV-1具有有效的活性。先前对raltegravir与rifampin并用的研究表明，raltegravir的血药浓度降低，可能是诱导UGT1A1继发的，UGT1A1是主要负责raltegravir代谢的酶。关于利福布丁（一种替代性利福霉素）对UGT1A1的诱导知之甚少。进行了利福平和利福布丁对UGT1A1的诱导效力的体外表征。体外研究表明，与利福平相比，利福布丁对UGT1A1信使RNA表达的诱导作用更弱。进行了一个固定序列的2周期临床交叉研究，以评估利福布汀对raltegravir血浆水平的影响：1期，每12小时400 mg raltegravir，持续4天;第二阶段，每12小时服用400毫克raltegravir，每天服用一次300毫克利福布汀，持续14天。在给药后0至12小时（AUC（0-12h））和90％置信区间（CI）的浓度-时间曲线下，raltegravir区域的几何平均比（GMR）（利福布汀和raltegravir与单独使用raltegravir并用）为1.19（0.86-1.63）; 12小时（C（12h））和90％CI的GMR浓度为0.80（0.68-0.94）;达到最大浓度（C（max））和90％CI的时间的GMR为1.39（0.87-2.21）。总体而言，利福布汀的共同给药不会在临床上有意义的程度上改变raltegravir的药代动力学。

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