Merck & Co, Inc, 126 E. Lincoln Ave, P.O. Box 2000, Rahway, NJ 07065, USA.
J Clin Pharmacol. 2011 Jun;51(6):943-50. doi: 10.1177/0091270010375959. Epub 2010 Sep 17.
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.
拉替拉韦是一种 HIV-1 整合酶链转移抑制剂，对 HIV-1 具有很强的活性。先前的研究表明，拉替拉韦与利福平联合使用时，拉替拉韦的血浆浓度降低，可能是由于 UGT1A1 的诱导，UGT1A1 是主要负责拉替拉韦代谢的酶。关于利福布汀（一种替代利福霉素）对 UGT1A1 的诱导作用知之甚少。进行了体外研究以评估利福平利福布汀对 UGT1A1 的诱导能力。体外研究表明，利福布汀对 UGT1A1 信使 RNA 表达的诱导作用不如利福平强。进行了一项固定序列、2 期、临床交叉研究，以评估利福布汀对拉替拉韦血浆水平的影响：第 1 期，4 天内每 12 小时服用 400 毫克拉替拉韦 4 次；第 2 期，每 12 小时服用 400 毫克拉替拉韦和每天 1 次 300 毫克利福布汀，共 14 天。拉替拉韦的 AUC(0-12h)和 90%置信区间（CI）的几何均数比值（GMR）（利福布汀和拉替拉韦联合给药与拉替拉韦单独给药相比）为 1.19（0.86-1.63）；浓度在 12 小时时的 GMR（C(12h)）和 90%CI 为 0.80（0.68-0.94）；和 C(max)的时间到最大浓度（GMR）和 90%CI 为 1.39（0.87-2.21）。总的来说，利福布汀的联合用药没有以临床有意义的程度改变拉替拉韦的药代动力学。
