Iwamoto M, Kost J T, Mistry G C, Wenning L A, Breidinger S A, Marbury T C, Stone J A, Gottesdiener K M, Bloomfield D M, Wagner J A
Merck & Co, Inc, RY34-A500, PO Box 2000, Rahway, NJ 07065-0900, USA.
J Clin Pharmacol. 2008 Jun;48(6):726-33. doi: 10.1177/0091270008318007. Epub 2008 Apr 25.
Raltegravir is a novel HIV-1 integrase inhibitor with potent in vitro activity (IC(95) = 31 nM in 50% human serum). A double-blind, randomized, placebo-controlled, double-dummy, 3-period, single-dose crossover study was conducted; subjects received single oral doses of 1600 mg raltegravir, 400 mg moxifloxacin, and placebo. The upper limit of the 2-sided 90% confidence interval for the QTcF interval placebo-adjusted mean change from baseline of raltegravir was less than 10 ms at every time point. For the raltegravir and placebo groups, there were no QTcF values >450 ms or change from baseline values >30 ms. A mean C(max) of approximately 20 muM raltegravir was attained, approximately 4-fold higher than the C(max) at the clinical dose. Moxifloxacin demonstrated an increase in QTcF at the 2-, 3-, and 4-hour time points. Administration of a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. A single supratherapeutic dose design may be appropriate for crossover thorough QTc studies.
雷特格韦是一种新型的HIV-1整合酶抑制剂，具有强大的体外活性（在50%人血清中IC(95)=31 nM）。进行了一项双盲、随机、安慰剂对照、双模拟、3期、单剂量交叉研究；受试者接受了1600 mg雷特格韦、400 mg莫西沙星和安慰剂的单次口服剂量。在每个时间点，雷特格韦经安慰剂调整后的QTcF间期从基线的平均变化的双侧90%置信区间上限均小于10 ms。对于雷特格韦组和安慰剂组，没有QTcF值>450 ms或从基线值变化>30 ms的情况。雷特格韦的平均C(max)约为20 μM，比临床剂量下的C(max)高约4倍。莫西沙星在2、3和4小时时间点显示QTcF增加。单次超治疗剂量的雷特格韦给药不会延长QTcF间期。单次超治疗剂量设计可能适用于交叉全面QTc研究。
