Adkison Kimberly K, Shachoy-Clark Anne, Fang Lei, Lou Yu, O'Mara Kathy, Berrey M Michelle, Piscitelli Stephen C
GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, North Carolina 27709, USA.
Antimicrob Agents Chemother. 2005 Jul;49(7):2802-6. doi: 10.1128/AAC.49.7.2802-2806.2005.
873140 is a novel CCR5 antagonist with potent in vitro anti-human immunodeficiency virus (HIV) activity. This study was a double-blind, randomized, placebo-controlled, single- and repeat-dose escalation investigation of the safety, pharmacokinetics, and food effect of 873140 in 70 adult subjects. During single-dose escalation, three cohorts (each composed of 10 subjects, with 8 subjects receiving the active drug and 2 subjects receiving the placebo [8 active and 2 placebo]) received doses of 50, 200, 400, 800, and 1,200 mg after an overnight fast, or 400 mg plus a standard high-fat breakfast in an alternating panel design. During repeat-dose escalation, four cohorts (each with 8 active and 2 placebo) received doses of 200, 400, 600, or 800 mg every 12 h (BID) for 8 days. Laboratory safety tests, vital signs, and electrocardiograms (ECGs) were performed at regular intervals, and blood samples were obtained for pharmacokinetics. Single and repeat doses of 50 mg to 800 mg were well tolerated, with no serious adverse events and no grade 3 or 4 adverse events. The mild-to-moderate side effects were primarily gastrointestinal and included abdominal cramping, nausea, and diarrhea. No specific trends in laboratory parameters or clinically significant ECG changes were noted. Plasma 873140 concentrations increased rapidly; the median time to maximum concentration of drug in serum was 1.75 to 5 h. The median area under the plasma concentration-time profile (AUC) and the maximum concentration of drug in serum (C(max)) ranged from 127 ng.h/ml and 24 ng/ml at 200 mg BID to 329 ng.h/ml and 100 ng/ml at 800 mg BID, respectively. Food consumption increased the AUC and C(max) by a mean of 1.7- and 2.2-fold, respectively. The pharmacokinetic and safety profile supports the continued investigation of 873140 with HIV-infected subjects.
873140是一种新型的CCR5拮抗剂，具有强大的体外抗人类免疫缺陷病毒（HIV）活性。本研究是一项双盲、随机、安慰剂对照、单剂量和重复剂量递增的研究，旨在评估70名成年受试者中873140的安全性、药代动力学和食物效应。在单剂量递增阶段，三个队列（每个队列由10名受试者组成，其中8名受试者接受活性药物，2名受试者接受安慰剂[8名活性药物和2名安慰剂]）在禁食过夜后接受50、200、400、800和1200 mg的剂量，或在交替分组设计中接受400 mg加标准高脂早餐。在重复剂量递增阶段，四个队列（每个队列有8名活性药物和2名安慰剂）每12小时（每日两次）接受200、400、600或800 mg的剂量，持续8天。定期进行实验室安全测试、生命体征和心电图（ECG）检查，并采集血样进行药代动力学分析。50 mg至800 mg的单剂量和重复剂量耐受性良好，无严重不良事件，也无3级或4级不良事件。轻度至中度副作用主要为胃肠道反应，包括腹部绞痛、恶心和腹泻。未观察到实验室参数的特定趋势或临床上显著的心电图变化。血浆873140浓度迅速升高；血清中药物达到最大浓度的中位时间为1.75至5小时。血浆浓度-时间曲线下面积（AUC）中位数和血清中药物最大浓度（C(max)）分别在每日两次200 mg时为127 ng·h/ml和24 ng/ml，在每日两次800 mg时为329 ng·h/ml和100 ng/ml。食物摄入分别使AUC和C(max)平均增加1.7倍和2.2倍。药代动力学和安全性概况支持对873140在HIV感染受试者中继续进行研究。
