A thorough QT study of guanfacine
A thorough QT study of guanfacine
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DOI：
10.5414/cp202065
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发表时间：
2015-04-01
影响因子：
0.8
通讯作者：
Ermer, James C.
中科院分区：
文献类型：
--
作者：
Martin, Patrick;Satin, Lawrence;Ermer, James C.
目的：胍法辛缓释剂（GXR）被批准用于治疗儿童和青少年的注意力缺陷/多动障碍。作为GXR临床开发的一部分，为了进一步探索胍法辛对QT间期的影响，进行了一项全面的胍法辛QT研究（ClinicalTrials.gov标识符：NCT 00672984）。研究方法：在这项双盲、3阶段、交叉试验中，健康成人（n = 83）在6个随机分配的序列中的1个序列中接受了立即释放胍法辛（治疗剂量（4 mg）和超治疗剂量（8 mg））、安慰剂和400 mg阿氟沙星（阳性对照）。提取连续12导联心电图，并在给药前和给药后24小时内评估胍法辛血浆浓度。使用2种方法校正QT间期：受试者特异性（QTcNi）和Fridericia（QTcF）。时间匹配分析检查了QTc间期的最大基线校正药物-安慰剂差异。结果：在QTcNi分析中，至第12小时的最大单侧95%置信上限（UCB）为1.94 ms（给药后12小时）。对于12小时QTcF分析，最大单侧95% UCB为10.34 ms（超治疗剂量给药后12小时），代表唯一单侧95% UCB > 10 ms。超治疗剂量给药后，在给药后5.0小时（中位数）达到最大胍法辛血浆浓度。测定灵敏度通过阿托沙星结果证实。在胍法辛治疗的受试者中，大多数治疗后出现的不良事件是轻度的（78.9%）;口干（65.8%）和头晕（61.8%）是最常见的。结论：使用个体化校正（QTcNi）调整心率后，治疗剂量和超治疗剂量的胍法辛均未延长QT间期至给药后12小时。胍法辛似乎不干扰与促心律失常药物相关的心脏复极化。
Objectives: Guanfacine extended-release (GXR) is approved for the treatment of attention-deficit/hyperactivity disorder in children and adolescents. As part of the clinical development of GXR, and to further explore the effect of guanfacine on QT intervals, a thorough QT study of guanfacine was conducted (ClinicalTrials.gov identifier: NCT00672984). Methods: In this double-blind, 3-period, crossover trial, healthy adults (n = 83) received immediate-release guanfacine (at therapeutic (4 mg) and supra-therapeutic (8 mg) doses), placebo, and 400 mg moxifloxacin (positive control) in 1 of 6 randomly assigned sequences. Continuous 12-lead electrocardiograms were extracted, and guanfacine plasma concentrations were assessed pre-dose and at intervals up to 24 hours post-dose. QT intervals were corrected using 2 methods: subject-specific (QTcNi) and Fridericia (QTcF). Time-matched analyses examined the largest, baseline-adjusted, drug-placebo difference in QTc intervals. Results: In the QTcNi analysis, the largest 1-sided 95% upper confidence bound (UCB) through hour 12 was 1.94 ms (12 hours post-dose). For the 12-hour QTcF analysis, the largest 1-sided 95% UCB was 10.34 ms (12 hours post-supratherapeutic dose), representing the only I-sided 95% UCB > 10 ms. Following the supra-therapeutic dose, maximum guanfacine plasma concentration was attained at 5.0 hours (median) post-dose. Assay sensitivity was confirmed by moxifloxacin results. Among guanfacine-treated subjects, most treatment-emergent adverse events were mild (78.9%); dry mouth (65.8%) and dizziness (61.8%) were most common. Conclusions: Neither therapeutic nor supra-therapeutic doses of guanfacine prolonged QT interval after adjusting for heart rate using individualized correction, QTcNi, through 12 hours post-dose. Guanfacine does not appear to interfere with cardiac repolarization of the form associated with pro-arrhythmic drugs.