Stone Nimalie D, Dunaway Shelia B, Flexner Charles, Tierney Camlin, Calandra Gary B, Becker Stephen, Cao Ying-Jun, Wiggins Ilene P, Conley Jeanne, MacFarland Ron T, Park Jeong-Gun, Lalama Christina, Snyder Sally, Kallungal Beatrice, Klingman Karin L, Hendrix Craig W
Johns Hopkins University School of Medicine, Division of Clinical Pharmacology, Harvey 502, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
Antimicrob Agents Chemother. 2007 Jul;51(7):2351-8. doi: 10.1128/AAC.00013-07. Epub 2007 Apr 23.
AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P < or = 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0- to 2.1-fold) in an E(max) model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070.
AMD070是一种口服CXCR4拮抗剂，具有体外抗X4嗜性1型人类免疫缺陷病毒的活性。30名空腹健康男性志愿者接受了口服剂量的AMD070，剂量范围从单次50毫克到每12小时（q12h）给予七次400毫克剂量。9名受试者在空腹和餐前接受了200毫克剂量。对受试者进行了安全性和药代动力学监测。AMD070耐受性良好，无严重不良事件。短暂性头痛（13名受试者）、神经认知症状（8名受试者）和胃肠道症状（7名受试者）是最常见的主诉。7名受试者出现窦性心动过速，2名有症状。AMD070血浆浓度在患者给药后1至2小时达到峰值。各队列的估计终末半衰期为11.2至15.9小时。未证明剂量比例关系。尿液中不到1%的药物以原形出现。食物使血清中药物的最大浓度以及浓度-时间曲线下从0至24小时的面积分别降低了70%和56%（P≤0.01）。在E(max)模型中，白细胞（WBC）的剂量依赖性升高显示最高比基线增加两倍（95%置信区间，2.0至2.1倍）。在健康志愿者中，AMD070耐受性良好，呈现出混合顺序药代动力学，食物减少了药物暴露。AMD070诱导了与剂量相关的白细胞升高，这归因于CXCR4阻断。使用白细胞增多作为CXCR4抑制的替代标志物，这种剂量反应关系表明本研究中使用的剂量在整个给药间隔内虽非最大但在体内具有活性。每12小时400毫克剂量的谷浓度超过了AMD070的体外抗病毒90%有效浓度。
