Cancer Science Institute of Singapore, National University of Singapore, 28 Medical Drive, Singapore 117456.
Antimicrob Agents Chemother. 2011 Sep;55(9):4090-5. doi: 10.1128/AAC.00593-11. Epub 2011 Jul 11.
Raltegravir is a potent inhibitor of HIV integrase. Persistently high intracellular concentrations of raltegravir may explain sustained efficacy despite high pharmacokinetic variability. We performed a pharmacokinetic study of healthy volunteers. Paired blood samples for plasma and peripheral blood mononuclear cells (PBMCs) were collected predose and 4, 8, 12, 24, and 48 h after a single 400-mg dose of raltegravir. Samples of plasma only were collected more frequently. Raltegravir concentrations were determined using liquid chromatography-mass spectrometry. The lower limits of quantitation for plasma and PBMC lysate raltegravir were 2 nmol/liter and 0.225 nmol/liter, respectively. Noncompartmental analyses were performed using WinNonLin. Population pharmacokinetic analysis was performed using NONMEM. Six male subjects were included in the study; their median weight was 67.4 kg, and their median age was 33.5 years. The geometric mean (GM) (95% confidence interval shown in parentheses) maximum concentration of drug (C(max)), area under the concentration-time curve from 0 to 12 h (AUC(0-12)), and area under the concentration-time curve from 0 h to infinity (AUC(0-∞)) for raltegravir in plasma were 2,246 (1,175 to 4,294) nM, 10,776 (5,770 to 20,126) nM · h, and 13,119 (7,235 to 23,788) nM · h, respectively. The apparent plasma raltegravir half-life was 7.8 (5.5 to 11.3) h. GM intracellular raltegravir C(max), AUC(0-12), and AUC(0-∞) were 383 (114 to 1,281) nM, 2,073 (683 to 6,290) nM · h, and 2,435 (808 to 7,337) nM · h (95% confidence interval shown in parentheses). The apparent intracellular raltegravir half-life was 4.5 (3.3 to 6.0) h. Intracellular/plasma ratios were stable for each patient without significant time-related trends over 48 h. Population pharmacokinetic modeling yielded an intracellular-to-plasma partitioning ratio of 11.2% with a relative standard error of 35%. The results suggest that there is no intracellular accumulation or persistence of raltegravir in PBMCs.
拉替拉韦是一种有效的 HIV 整合酶抑制剂。尽管药代动力学变异性很大，但细胞内持续高浓度的拉替拉韦可能解释了其持续的疗效。我们对健康志愿者进行了一项药代动力学研究。在单次给予 400 毫克拉替拉韦后，采集了 4、8、12、24 和 48 小时的配对血样，用于血浆和外周血单核细胞（PBMC）。更多地采集了仅用于血浆的样本。使用液相色谱-质谱法测定拉替拉韦浓度。血浆和 PBMC 裂解物拉替拉韦的定量下限分别为 2 毫摩尔/升和 0.225 毫摩尔/升。使用 WinNonLin 进行非房室分析。使用 NONMEM 进行群体药代动力学分析。该研究纳入了 6 名男性受试者；他们的中位体重为 67.4 千克，中位年龄为 33.5 岁。拉替拉韦在血浆中的几何均数（GM）（括号中显示置信区间）最大浓度（C(max)）、从 0 至 12 小时的浓度-时间曲线下面积（AUC(0-12)）和从 0 小时至无穷大的浓度-时间曲线下面积（AUC(0-∞)）分别为 2246（1175 至 4294）纳摩尔/升、10776（5770 至 20126）纳摩尔/小时和 13119（7235 至 23788）纳摩尔/小时。拉替拉韦在血浆中的表观半衰期为 7.8（5.5 至 11.3）小时。GM 细胞内拉替拉韦 C(max)、AUC(0-12)和 AUC(0-∞)分别为 383（114 至 1281）纳摩尔/升、2073（683 至 6290）纳摩尔/小时和 2435（808 至 7337）纳摩尔/小时（括号中显示置信区间）。细胞内拉替拉韦的表观半衰期为 4.5（3.3 至 6.0）小时。在 48 小时内，每个患者的细胞内/血浆比值均稳定，没有明显的时间相关趋势。群体药代动力学模型得出细胞内到血浆的分配比为 11.2%，相对标准误差为 35%。结果表明，在 PBMC 中没有拉替拉韦的细胞内蓄积或持续存在。
