Cao Ying Jun, Flexner Charles W, Dunaway Shelia, Park Jeong-Gun, Klingman Karin, Wiggins Ilene, Conley Jeanne, Radebaugh Christine, Kashuba Angela D, MacFarland Ron, Becker Stephen, Hendrix Craig W
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Antimicrob Agents Chemother. 2008 May;52(5):1630-4. doi: 10.1128/AAC.01460-07. Epub 2008 Feb 19.
AMD070, a CXCR4 antagonist, has demonstrated antiretroviral activity in human immunodeficiency virus-infected patients. Since AMD070 is a substrate of cytochrome P450 3A4 and P-glycoprotein, both of which may be affected by ritonavir, we tested for a ritonavir effect on AMD070 pharmacokinetics. Subjects were given a single 200-mg dose of AMD070 on days 1, 3, and 17. Ritonavir (100 mg every 12 h) was dosed from day 3 to day 18. Blood samples to test for AMD070 concentrations were collected over 48 h after each administration of AMD070. Twenty-three male subjects were recruited. Among them, 21 completed the study, and 2 were discontinued for reasons other than safety. All adverse events were grade 2 or lower. AMD070 alone had the following pharmacokinetic features, given as medians (ranges): 3 h (0.5 to 4 h) for the time to peak blood concentration, 256 ng/ml (41 to 845 ng/ml) for the peak concentration (C(max)), 934 h x ng/ml (313 to 2,127 h x ng/ml) for the area under the concentration-time curve from 0 h to infinity (AUC(0-infinity)), 214 liters/h (94 to 639 liters/h) for apparent body clearance, and 4,201 liters (1,996 to 9,991 liters) for the apparent volume of distribution based on the terminal phase. The initial doses of ritonavir increased the C(max) of AMD070 [geometric mean (90% confidence interval)] by 39% (3 to 89%) and the AUC(0-infinity) by 60% (29 to 100%). After 14 days of ritonavir dosing, the pharmacokinetic changes in AMD070 persisted. The plasma pharmacokinetics of ritonavir were consistent with previous reports. It is concluded that AMD070 concentrations were increased with concomitant ritonavir dosing for 14 days in healthy volunteers.
AMD070是一种CXCR4拮抗剂，已在人类免疫缺陷病毒感染患者中显示出抗逆转录病毒活性。由于AMD070是细胞色素P450 3A4和P-糖蛋白的底物，而这两者都可能受利托那韦影响，因此我们测试了利托那韦对AMD070药代动力学的作用。在第1天、第3天和第17天，受试者接受单次200毫克剂量的AMD070。从第3天至第18天给予利托那韦（每12小时100毫克）。每次给予AMD070后48小时内采集血样以检测AMD070浓度。招募了23名男性受试者。其中，21人完成了研究，2人因安全以外的原因退出。所有不良事件均为2级或以下。单独使用AMD070具有以下药代动力学特征，以中位数（范围）表示：血药浓度达峰时间为3小时（0.5至4小时），峰浓度（C(max)）为256纳克/毫升（41至845纳克/毫升），0小时至无穷大的浓度-时间曲线下面积（AUC(0-无穷大)）为934小时×纳克/毫升（313至2127小时×纳克/毫升），表观机体清除率为214升/小时（94至639升/小时），基于终末相的表观分布容积为4201升（1996至9991升）。利托那韦的初始剂量使AMD070的C(max) [几何均值（90%置信区间）]增加了39%（3%至89%），AUC(0-无穷大)增加了60%（29%至100%）。利托那韦给药14天后，AMD070的药代动力学变化持续存在。利托那韦的血浆药代动力学与先前报告一致。得出的结论是，在健康志愿者中，利托那韦连续给药14天会使AMD070浓度升高。
